Gcn5 and mTORC1 mediated regulation of autophagy controls Drosophila blood cell homeostasis

Drosophila hematopoiesis occurs in two different waves: the first wave occurs in the embryonic stages in the procephalic mesoderm, giving rise to both circulating and sessile pools of hemocytes. While the second wave of definitive hematopoiesis begins in the dorsal mesoderm, giving rise to the lymph gland (LG), the larval hematopoietic organ (Banerjee et al., 2019; Evans et al., 2003). The larval LG can be divided into functionally distinct regions: the Posterior Signaling Center (PSC), which acts as the stem cell niche producing signals that are not only required for maintaining the prohemocytes but also for priming them toward differentiation. The medullary zone (MZ) is made up of prohemocytes (hematopoietic progenitors) that are capable of differentiating into three differentiated blood cell types, namely plasmatocytes, crystal cells, and lamellocytes. The cortical zone (CZ) houses the differentiated blood cell population (Jung et al., 2005). Single-cell sequencing efforts have identified heterogeneity among the developing hemocytes in the LG and have discovered previously unreported hemocyte types like adipohemocytes, stem-like prohemocytes, intermediate prohemocytes, and early lamellocytes, suggesting that there is a lot of heterogeneity in the cell types present within the LG; for example, the subsets identified within the progenitors: core, distal, and intermediate (Cho et al., 2020; Kharrat et al., 2022). These recent single-cell sequencing-based studies show that the LG is a complex organ with multiple hemocyte types and consists of an intricate array of signals that regulate them (Cho et al., 2020; Girard et al., 2021).

The cellular fate of prohemocytes in the medullary zone is intricately controlled by a set of extrinsic and intrinsic signals. Multiple signaling pathways like the JAK/STAT, Hedgehog, Wingless, and Dpp have been reported to play an important role in prohemocyte maintenance (Dey et al., 2016; Khadilkar et al., 2014; Khadilkar et al., 2017; Khadilkar et al., 2020; Khadilkar and Tanentzapf, 2019; Krzemień et al., 2007; Mandal et al., 2007; Sinenko et al., 2009; Sinha et al., 2013). Stem cell and tissue homeostasis is closely linked to the nutritional status of the organism. There is increasing evidence indicating the involvement of nutrient signals in stem/progenitor cell fate (Amcheslavsky et al., 2009; Chell and Brand, 2010; McLeod et al., 2010; Sousa-Nunes et al., 2011). Drosophila hematopoietic progenitors are capable of sensing systemic and nutritional cues. Starvation has been shown to alter the homeostatic balance in the LG, mimicking an inflammatory response-like scenario causing excessive differentiation of blood cells (Shim et al., 2012). Also, perturbation of key nutrient sensing pathways like the IIS/Tor signaling has been shown to affect niche numbers as well as progenitor differentiation (Benmimoun et al., 2012). More specifically, TORC1 has been shown to play an important role during Drosophila hematopoiesis. TORC1 activity has been shown to promote the proliferation and expansion of progenitor pools (Dragojlovic-Munther and Martinez-Agosto, 2012). Knocking down TOR signaling components in the Drosophila hematopoietic niche has shown to cause a cell-autonomous reduction in the niche numbers. Activation of Tor signaling, on the other hand, results in excess progenitor differentiation. This shows that a fine-tuning of the nutrient-sensing pathways is important for progenitor maintenance (Tokusumi et al., 2012). Autophagy, a cell intrinsic process, is also known to be responsive to nutritional status and stress. Autophagy ensures cellular homeostasis by removing intracellular waste material, replacing old and damaged organelles, and sustaining cell survival during nutrient-deprived conditions (Das et al., 2012; Lu et al., 2022). mTOR (molecular target of rapamycin) is an important regulator of autophagy. mTORC1 inhibits autophagy in nutrient-replete conditions by targeting either initiation, expansion, or termination of autophagy (Dossou and Basu, 2019). Several studies indicate that autophagy is essential for the maintenance of hematopoietic stem cells (HSCs; Ho et al., 2017; Mortensen et al., 2011; Warr et al., 2013). There have been several reports that investigate the role of key autophagy genes in hematopoiesis and show that mice lacking functional autophagy genes like Atg7, Atg12, or FIP200 lead to an exhaustion of the HSC pool, especially long-term HSCs, thus showing that autophagy is critical for HSC maintenance (Mortensen et al., 2011; Gomez-Puerto et al., 2016; Liu et al., 2010). Furthermore, HSCs lacking Atg12 displayed phenotypes similar to aged HSCs, viz. increased mitochondrial content, heightened metabolic activity, myeloid differentiation bias (Ho et al., 2017). Similarly, autophagy genes are shown to affect Drosophila hematopoiesis; it has been shown that Atg6 mutants show an enlarged LG and possess elevated blood cell numbers (Shravage et al., 2013). Perturbing autophagy by knocking down Atg1 affected hemocyte spreading and recruitment to the wound site (Kadandale et al., 2010). Inhibiting Atg2 induced melanotic nodule formation, impaired the ability to respond to bacterial infection by altering the expression of AMP (Anti-Microbial Peptides) genes, as well as disrupting phagocytosis (Qin et al., 2023). Misregulation of the autophagic process can lead to leukemogenesis (Koschade and Brandts, 2020). Though the role of autophagy has been explored in mammalian hematopoiesis, its role and mechanisms it controls during Drosophila hematopoiesis is unexplored. There are various nutrient sensors that can sense systemic nutrient signals and regulate cellular processes like autophagy. In this study, we report that General control non-depressible 5 (GCN5), a histone acetyltransferase (HAT), regulates the process of autophagy during hematopoiesis through its non-histone acetylation target, Transcription Factor EB (TFEB).

GCN5 is the first nuclear HAT to be identified with function in transcriptional regulation by serving as a key subunit in transcriptional coactivator complexes like SAGA (Spt-Ada-Gcn5-acetyltransferase) and ATAC (Ada-2A-containing) (Brownell et al., 1996; Grant et al., 1999; Nagy and Tora, 2007). The transfer of acetyl group to the lysine residues of histones mediates HAT activity (Pearson et al., 2008). The primary acetylation site of Gcn5 is lysine 14 of Histone 3 (H3K14), whereas other lysine residues of Histone 3, like H3K9, H3K18, H3K23, and H3K27, are also found to be acetylated by Gcn5 (Kuo and Andrews, 2013). Recent studies reported the additional role of Gcn5 in histone succinylation as well as crotonylation (Kollenstart et al., 2019; Wang et al., 1997; Wang et al., 2017). Gcn5 has important functions in the extension of lifespan (Huang et al., 2020), metabolism (Lerin et al., 2006), cellular differentiation (Gao et al., 2017), cell proliferation and growth (Downey et al., 2013), neuronal apoptosis (Wu et al., 2017), and DNA damage response (Guo et al., 2011). GCN5 acts as an oncoprotein in cancer, and its inhibition can rescue cancer phenotypes in various cancers, namely hepatocellular carcinoma, glioma, and non-small cell lung carcinoma (Liu et al., 2015; Majaz et al., 2016; Mustachio et al., 2019). Gcn5 is over-expressed in acute myeloid leukemia (AML) and is needed for the survival of AML cell lines (Tzelepis et al., 2016). Aberrant acetylation of H3K9 by GCN5 leads to all-trans retinoic acid (ATRA) resistance in non-APL AML, thereby preventing the maturation of myeloid blasts and maintaining them in a leukemic state (Kahl et al., 2019). GCN5 plays a role in drug resistance in the leukemic early drug-resistant population, where it interacts with ATM, thereby recruiting ATM to the DNA damage site (Salunkhe et al., 2018). With an evolutionary well-conserved structure and function, the significance of Gcn5 in different cellular processes can be studied using a variety of model organisms (Wang et al., 1997). Drosophila has only one homolog of Gcn5 (dGCN5), hence making it an efficient model to study the functions of Gcn5 (Smith et al., 1998). In Drosophila, loss of Gcn5 function affects developmental processes like oogenesis and metamorphosis (Carré et al., 2005). Gcn5 plays an important role in germline stem cell maintenance (Liu et al., 2017). Other than the developmental processes, Gcn5 was shown to regulate a cellular process like autophagy by targeting TFEB, a non-histone acetylation target of Gcn5 that activates genes responsible for autophagosomal and lysosome biogenesis (Wang et al., 2020). mTORC1 regulates autophagy not only through the initiator kinase, Ulk1 arm, but also through inhibitory phosphorylation of TFEB (Rabanal-Ruiz et al., 2017). In the context of hematopoiesis, Gcn5 is necessary for T-cell development and function, and deletion of Gcn5 could affect the development of immune cells in vertebrates (Gao et al., 2017). Gcn5 expression increases during the differentiation phase of human CD34 cells, indicating an important role of Gcn5 in erythroid differentiation (Woo et al., 2011). Although there are studies demonstrating the role of Gcn5 in leukemogenesis, there is a paucity of information on its role in physiological hematopoiesis. In Drosophila, a study reported that loss of a HAT like Gcn5 or Chameau phenocopies the differentiation defect seen upon loss of function of molecules regulating fatty acid oxidation (Tiwari et al., 2020). There are no other studies that have explored the role of Gcn5 during normal hematopoiesis in Drosophila.

Here, we show that Gcn5 plays an essential role in regulating blood cell homeostasis in the Drosophila LG. Analysis of gcn5 mutants, cellular subset-specific modulation of Gcn5 levels in the LG, and by utilizing structure function approaches in the LG, we show that Gcn5 function is important for developmental hematopoiesis. Our results demonstrate that modulation of Gcn5 levels alters blood cell homeostasis via its regulation of autophagy. We show that autophagy plays a critical role in the LG by controlling blood cell differentiation. Gcn5 acts as a nutrient sensor and negatively regulates autophagy through its non-histone acetylation target, TFEB. Additionally, our findings indicate that modulation of mTORC1 activity can regulate Gcn5 levels and perturb LG hematopoiesis. mTORC1 overrides the effect exerted by Gcn5 in regulating LG hematopoiesis. Taken together, we suggest that the Gcn5–mTORC1–TFEB signaling axis mediated control of autophagy is required for maintaining blood cell homeostasis in Drosophila.

Gcn5 is highly expressed in (AML) and helps in the maintenance of immature leukemic blasts (Kahl et al., 2019; Salunkhe et al., 2018). While its function in the context of leukemia is well studied, Gcn5 function during physiological hematopoiesis is unexplored. Here, we explore Gcn5 role during normal physiological hematopoiesis in Drosophila. Our work shows that Gcn5, an HAT, plays an important role during Drosophila LG hematopoiesis. We find that Gcn5 is expressed in all the LG cellular subsets and its levels are critical for controlling hematopoiesis. Structure–function analysis of Gcn5 shows that expression of Gcn5 lacking any of its constituent domains in wild type genetic background results in a dominant negative phenotype in the LG. Our results indicate that optimum levels of Gcn5 are critical in the prohemocytes as excess Gcn5 results in increased blood cell differentiation. We find that the number of PSC cells is altered either in an autonomous or non-autonomous manner where PSC-specific or non-PSC-specific modulation of Gcn5 levels results in changes in niche cell numbers which could be due to perturbation of signaling pathways like Insulin, mTOR, Dpp which are critical in maintaining the niche cells (Benmimoun et al., 2012; Pennetier et al., 2012) which needs further exploration. Our results also suggest that niche cell numbers are reduced in the gcn5 null mutants and transheterozygotes of gcn5 mutant alleles which we speculate could be due to abrogation of local niche supporting pathways such as mTOR signaling, which is known to be a critical regulator of PSC maintenance. Since these are whole animal mutants, there could be a number of signals that could be perturbed which needs to be investigated. Our results show that there is increased differentiation in gcn5 mutant alleles and transheterozygotes which could be due to abrogation of various signaling pathways that might be affected systemically and LGs are highly sensitive to systemic signals which could result in aberrant hematopoiesis which needs further investigation. Also, we observe that PSC numbers are modulated upon perturbation of Gcn5 using hmlΔ-Gal4, uncovering a non-cell-autonomous effect on the niche which would need further investigation to determine if it represents a feedback mechanism. Further, we find that Gcn5 acts as a nutrient sensor and its levels are critical for controlling the autophagic flux in the LG. In order to investigate whether autophagy players regulate LG hematopoiesis, we carried out a targeted genetic analysis of key autophagy regulators and our results indicate that disrupting autophagy abrogates LG hematopoiesis. Increased Gcn5 levels in the hemocytes led to a decrease in the autophagic flux whereas depleting Gcn5 resulted in increased autophagy. LG phenotypes upon genetic modulation of Gcn5 corroborate with the phenotypes obtained upon perturbation of autophagy regulators, providing a potential parallel mechanism.

Since mTORC1 regulates autophagy in response to nutrient conditions, we investigated whether modulating mTORC1 activity affects hematopoiesis. Our data elucidates that modulating mTORC1 activity regulates hematopoiesis, and these effects are consistent with observations obtained upon genetic modulation of autophagy. Inhibiting mTORC1 activity using Rapamycin results in Gcn5 downregulation, suggesting a potential regulatory connection between mTORC1 signaling and Gcn5 expression. One of the common molecular links through which both mTORC1 and Gcn5 could potentially regulate autophagy is through TFEB, a member of the microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) family (Song et al., 2021). Our results demonstrate that mTORC1 can override Gcn5 in regulating LG hematopoiesis. Although we show this override effect with chemical intervention, further genetic epistasis-based analysis will further strengthen this data, providing important insights. Overall, our data points to a model where Gcn5 and mTORC1 control autophagy to regulate Drosophila LG hematopoiesis.

Expression analysis of Gcn5 in the LG indicates that Gcn5 is expressed in all the LG cellular sub-populations. gcn5 mutant alleles display loss of blood cell homeostasis. Increase in plasmatocyte or crystal cell differentiation could be due to a contribution of systemic signals that are altered upon loss of Gcn5 in the entire organism, as the LG is capable of responding to external stimuli (Shim et al., 2013). gcn5 mutant alleles either in homozygous or trans-heterozygous conditions show an increased accumulation of DNA damage indicative of its role in DNA damage repair pathways (Guo et al., 2011; Zhao et al., 2017). Prohemocyte-specific over-expression of Gcn5 leads to increased plasmatocyte as well as crystal cell differentiation, whereas depletion of Gcn5 levels has no significant effect on differentiation. hmldelta-Gal4 mediated CZ-specific over-expression of Gcn5 resulted in a cell-autonomous increase in crystal cell differentiation, whereas Gcn5 knockdown had no effect. These results suggest that Gcn5 acts in a lineage-specific manner cell-autonomously in the differentiated hemocytes. Higher levels of Gcn5 skew the balance toward increased blood cell differentiation. Higher Gcn5 expression has been observed previously in many carcinomas and leukemia, promoting cell proliferation, growth, and cancer progression (Liu et al., 2015; Majaz et al., 2016; Mustachio et al., 2019; Tzelepis et al., 2016; Kahl et al., 2019; Salunkhe et al., 2018). Structure–function analysis shows that expression of Gcn5 lacking the Bromo or Ada domain in the wildtype genetic background results in a dominant negative phenotype in terms of the maintenance of prohemocyte population itself and plasmatocyte differentiation, whereas expression of Gcn5 lacking HAT or Bromo or Ada results in a dominant negative effect on crystal cell differentiation, indicating that the constituent domains of Gcn5 might be playing specific functions in regulating various aspects of LG hematopoiesis via specific interacting partners. The constituent domains in Gcn5 could be performing unique functions in regulating homeostasis based on their interacting partners, which needs to be explored. Gcn5 responds to changes in cellular energetic and metabolic states (Mutlu and Puigserver, 2021). Gcn5, via its non-histone acetylation target, TFEB, is capable of regulating autophagy, which is directly linked to the nutritional status of the cell. Since Gcn5 is capable of sensing nutrient signals, its role in regulating the sensing by blood progenitors needs to be studied in detail and if it has any other potential crosstalk with signaling pathways that act downstream of nutrient and metabolic signals. TFEB acetylation by Gcn5 is inhibitory for TFEB, as it prevents its dimerization and hence nuclear translocation. Upon nuclear translocation, TFEB activates genes responsible for autophagosome and lysosome biogenesis (Wang et al., 2020).

In order to probe whether Gcn5 mediated regulation is due to its control over autophagy, we probed whether perturbing Gcn5 has any effect on the autophagic flux in the hemocytes. Our results suggest that depletion of Gcn5 leads to an upregulation of autophagy, increasing the flux, whereas over-expression of Gcn5 results in downregulation of autophagy, lowering the autophagic flux. These observations were intriguing, as this establishes an important role of autophagy in maintaining LG homeostasis. We investigated this further to find out if there is a direct link between autophagy regulators (Atg genes), including TFEB, in controlling LG hematopoiesis. Genetic perturbation of the autophagy pathway regulators or TFEB in the prohemocytes consistently accelerated blood cell differentiation. Chemical inhibition of autophagy induced by Chloroquine also recapitulates this phenotype. There is literature indicating a critical role for autophagy in the development of the blood system, self-renewal of HSCs, and their mobilization (Ho et al., 2017; Gomez-Puerto et al., 2016; Liu et al., 2010; Koschade and Brandts, 2020). Our observations on the role of autophagy in Drosophila LG hematopoiesis support these findings. We then moved on to test if mTORC1 could regulate hematopoiesis. Chemical or genetic modulation of mTORC1 activity, which is a master molecule that regulates autophagy, alters LG hematopoiesis. mTORC1 activity regulates Gcn5 levels, as inhibition of mTORC1 activity resulted in lower levels of Gcn5.

mTORC1 regulates autophagy via two arms – one via the initiator kinase, Ulk1, in response to either nutrient depletion or replete conditions via inhibitory phosphorylation of TFEB (Ganley et al., 2009; Jung et al., 2009; Kim et al., 2011). TFEB phosphorylation by mTORC1 subjects it to degradation, thereby inhibiting autophagy (Martina et al., 2012). Since TFEB is the common link that is regulated by both mTORC1 and Gcn5, we wanted to understand whether one is epistatic to the other in controlling hematopoiesis. We find that mTORC1 can override Gcn5 in controlling hematopoiesis by a chemical intervention approach. Although further genetic epistasis experiments will be needed to show that this effect is indeed by acting upstream and controlling Gcn5. We speculate that during physiological hematopoiesis, a balance between phosphorylation and acetylation of TFEB mediated by mTORC1 and Gcn5, respectively, regulates levels of autophagy, which needs further experimental investigation. Perturbation of Gcn5 or mTORC1 activity could disturb this balance, thereby deregulating hematopoiesis. Our findings shed light on the importance of the non-histone acetylation function of Gcn5 in hematopoiesis. This could especially be important as the LG prohemocytes are known to respond to cell intrinsic and extrinsic nutrient signals (Shim et al., 2012). The nutrient state could regulate autophagy, thereby dictating the differentiation trajectory of the precursor cells. Since Gcn5 is highly expressed in AML (Kahl et al., 2019; Salunkhe et al., 2018), it becomes important to understand how Gcn5 level is regulated and what cellular processes Gcn5 is capable of regulating in order to control tissue homeostasis. Our work sheds novel insights on the role of Gcn5 during normal hematopoiesis. Our results demonstrate that organismal Gcn5 levels fluctuate in response to dietary challenges. Gcn5 could be acting as a downstream effector that translates systemic metabolic changes to modulate autophagic flux in blood cells. It would be interesting to understand the kind of nutrient signals to which Gcn5 is capable of responding and whether Gcn5 has any crosstalk with other nutrient sensing molecules and pathways other than mTORC1. The nutrient sensing function of Gcn5, given the ability of hemocytes to respond to nutrient cues, warrants further investigation. We show that Gcn5 fine-tunes autophagy in conjunction with mTORC1, where mTORC1 activity is capable of regulating Gcn5 and can override its function in modulating autophagy. Our findings shed an important and broad role of Gcn5 and mTORC1 in controlling autophagy that ultimately regulates Drosophila hematopoiesis (Figure 9).

All the data related to the manuscript is within the manuscript file, source data files and figures.

1. 1. Amcheslavsky A
   2. Jiang J
   3. Ip YT

   (2009) Tissue damage-induced intestinal stem cell division in Drosophila

   Cell Stem Cell 4:49–61.

   https://doi.org/10.1016/j.stem.2008.10.016

   • PubMed
   • Google Scholar
2. 1. Banerjee U
   2. Girard JR
   3. Goins LM
   4. Spratford CM

   (2019) Drosophila as a genetic model for hematopoiesis

   Genetics 211:367–417.

   https://doi.org/10.1534/genetics.118.300223

   • Google Scholar
3. 1. Benmimoun B
   2. Polesello C
   3. Waltzer L
   4. Haenlin M

   (2012) Dual role for Insulin/TOR signaling in the control of hematopoietic progenitor maintenance in Drosophila

   Development 139:1713–1717.

   https://doi.org/10.1242/dev.080259

   • PubMed
   • Google Scholar
4. 1. Brownell JE
   2. Zhou J
   3. Ranalli T
   4. Kobayashi R
   5. Edmondson DG
   6. Roth SY
   7. Allis CD

   (1996) Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation

   Cell 84:843–851.

   https://doi.org/10.1016/s0092-8674(00)81063-6

   • PubMed
   • Google Scholar
5. 1. Carré C
   2. Szymczak D
   3. Pidoux J
   4. Antoniewski C

   (2005) The histone H3 acetylase dGcn5 is a key player in Drosophila melanogaster metamorphosis

   Molecular and Cellular Biology 25:8228–8238.

   https://doi.org/10.1128/MCB.25.18.8228-8238.2005

   • PubMed
   • Google Scholar
6. 1. Chell JM
   2. Brand AH

   (2010) Nutrition-responsive glia control exit of neural stem cells from quiescence

   Cell 143:1161–1173.

   https://doi.org/10.1016/j.cell.2010.12.007

   • PubMed
   • Google Scholar
7. 1. Chen C
   2. Liu Y
   3. Liu R
   4. Ikenoue T
   5. Guan KL
   6. Liu Y
   7. Zheng P

   (2008) TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species

   The Journal of Experimental Medicine 205:2397–2408.

   https://doi.org/10.1084/jem.20081297

   • PubMed
   • Google Scholar
8. 1. Cho B
   2. Yoon S-H
   3. Lee D
   4. Koranteng F
   5. Tattikota SG
   6. Cha N
   7. Shin M
   8. Do H
   9. Hu Y
   10. Oh SY
   11. Lee D
   12. Vipin Menon A
   13. Moon SJ
   14. Perrimon N
   15. Nam J-W
   16. Shim J

   (2020) Single-cell transcriptome maps of myeloid blood cell lineages in Drosophila

   Nature Communications 11:4483.

   https://doi.org/10.1038/s41467-020-18135-y

   • PubMed
   • Google Scholar
9. 1. Das G
   2. Shravage BV
   3. Baehrecke EH

   (2012) Regulation and function of autophagy during cell survival and cell death

   Cold Spring Harbor Perspectives in Biology 4:a008813.

   https://doi.org/10.1101/cshperspect.a008813

   • PubMed
   • Google Scholar
10. 1. Dey NS
    2. Ramesh P
    3. Chugh M
    4. Mandal S
    5. Mandal L

    (2016) Dpp dependent hematopoietic stem cells give rise to Hh dependent blood progenitors in larval lymph gland of Drosophila

    eLife 5:e18295.

    https://doi.org/10.7554/eLife.18295

    • PubMed
    • Google Scholar
11. 1. Dossou AS
    2. Basu A

    (2019) The emerging roles of mTORC1 in macromanaging autophagy

    Cancers 11:1422.

    https://doi.org/10.3390/cancers11101422

    • PubMed
    • Google Scholar
12. 1. Downey M
    2. Knight B
    3. Vashisht AA
    4. Seller CA
    5. Wohlschlegel JA
    6. Shore D
    7. Toczyski DP

    (2013) Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1

    Current Biology 23:1638–1648.

    https://doi.org/10.1016/j.cub.2013.06.050

    • PubMed
    • Google Scholar
13. 1. Dragojlovic-Munther M
    2. Martinez-Agosto JA

    (2012) Multifaceted roles of PTEN and TSC orchestrate growth and differentiation of Drosophila blood progenitors

    Development 139:3752–3763.

    https://doi.org/10.1242/dev.074203

    • PubMed
    • Google Scholar
14. 1. Evans CJ
    2. Hartenstein V
    3. Banerjee U

    (2003) Thicker than blood

    Developmental Cell 5:673–690.

    https://doi.org/10.1016/S1534-5807(03)00335-6

    • Google Scholar
15. 1. Galluzzi L
    2. Yamazaki T
    3. Kroemer G

    (2018) Linking cellular stress responses to systemic homeostasis

    Nature Reviews. Molecular Cell Biology 19:731–745.

    https://doi.org/10.1038/s41580-018-0068-0

    • PubMed
    • Google Scholar
16. 1. Ganley IG
    2. Lam DH
    3. Wang J
    4. Ding X
    5. Chen S
    6. Jiang X

    (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy

    The Journal of Biological Chemistry 284:12297–12305.

    https://doi.org/10.1074/jbc.M900573200

    • PubMed
    • Google Scholar
17. 1. Gao B
    2. Kong Q
    3. Zhang Y
    4. Yun C
    5. Dent SYR
    6. Song J
    7. Zhang DD
    8. Wang Y
    9. Li X
    10. Fang D

    (2017) The histone acetyltransferase Gcn5 positively regulates T cell activation

    Journal of Immunology 198:3927–3938.

    https://doi.org/10.4049/jimmunol.1600312

    • PubMed
    • Google Scholar
18. 1. Girard JR
    2. Goins LM
    3. Vuu DM
    4. Sharpley MS
    5. Spratford CM
    6. Mantri SR
    7. Banerjee U

    (2021) Paths and pathways that generate cell-type heterogeneity and developmental progression in hematopoiesis

    eLife 10:e67516.

    https://doi.org/10.7554/eLife.67516

    • PubMed
    • Google Scholar
19. 1. Gomez-Puerto MC
    2. Folkerts H
    3. Wierenga ATJ
    4. Schepers K
    5. Schuringa JJ
    6. Coffer PJ
    7. Vellenga E

    (2016) Autophagy proteins ATG5 and ATG7 are essential for the maintenance of human CD34(+) hematopoietic stem-progenitor cells

    Stem Cells 34:1651–1663.

    https://doi.org/10.1002/stem.2347

    • PubMed
    • Google Scholar
20. 1. Grant PA
    2. Eberharter A
    3. John S
    4. Cook RG
    5. Turner BM
    6. Workman JL

    (1999) Expanded lysine acetylation specificity of Gcn5 in native complexes

    The Journal of Biological Chemistry 274:5895–5900.

    https://doi.org/10.1074/jbc.274.9.5895

    • PubMed
    • Google Scholar
21. 1. Guo R
    2. Chen J
    3. Mitchell DL
    4. Johnson DG

    (2011) GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damage

    Nucleic Acids Research 39:1390–1397.

    https://doi.org/10.1093/nar/gkq983

    • PubMed
    • Google Scholar
22. 1. Han Y
    2. Zhao H
    3. Li G
    4. Jia J
    5. Guo H
    6. Tan J
    7. Sun X
    8. Li S
    9. Ran Q
    10. Bai C
    11. Gu Y
    12. Li Z
    13. Guan H
    14. Gao S
    15. Zhou PK

    (2024) GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity

    British Journal of Cancer 130:1621–1634.

    https://doi.org/10.1038/s41416-024-02636-4

    • PubMed
    • Google Scholar
23. 1. Ho TT
    2. Warr MR
    3. Adelman ER
    4. Lansinger OM
    5. Flach J
    6. Verovskaya EV
    7. Figueroa ME
    8. Passegué E

    (2017) Autophagy maintains the metabolism and function of young and old stem cells

    Nature 543:205–210.

    https://doi.org/10.1038/nature21388

    • PubMed
    • Google Scholar
24. 1. Huang B
    2. Zhong D
    3. Zhu J
    4. An Y
    5. Gao M
    6. Zhu S
    7. Dang W
    8. Wang X
    9. Yang B
    10. Xie Z

    (2020) Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines

    Aging Cell 19:e13129.

    https://doi.org/10.1111/acel.13129

    • PubMed
    • Google Scholar
25. 1. Ianniciello A
    2. Helgason GV

    (2022) Targeting ULK1 in cancer stem cells: insight from chronic myeloid leukemia

    Autophagy 18:1734–1736.

    https://doi.org/10.1080/15548627.2022.2041152

    • PubMed
    • Google Scholar
26. 1. Jung SH
    2. Evans CJ
    3. Uemura C
    4. Banerjee U

    (2005) The Drosophila lymph gland as a developmental model of hematopoiesis

    Development 132:2521–2533.

    https://doi.org/10.1242/dev.01837

    • PubMed
    • Google Scholar
27. 1. Jung CH
    2. Jun CB
    3. Ro SH
    4. Kim YM
    5. Otto NM
    6. Cao J
    7. Kundu M
    8. Kim DH

    (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery

    Molecular Biology of the Cell 20:1992–2003.

    https://doi.org/10.1091/mbc.e08-12-1249

    • PubMed
    • Google Scholar
28. 1. Kadandale P
    2. Stender JD
    3. Glass CK
    4. Kiger AA

    (2010) Conserved role for autophagy in Rho1-mediated cortical remodeling and blood cell recruitment

    PNAS 107:10502–10507.

    https://doi.org/10.1073/pnas.0914168107

    • PubMed
    • Google Scholar
29. 1. Kahl M
    2. Brioli A
    3. Bens M
    4. Perner F
    5. Kresinsky A
    6. Schnetzke U
    7. Hinze A
    8. Sbirkov Y
    9. Stengel S
    10. Simonetti G
    11. Martinelli G
    12. Petrie K
    13. Zelent A
    14. Böhmer FD
    15. Groth M
    16. Ernst T
    17. Heidel FH
    18. Scholl S
    19. Hochhaus A
    20. Schenk T

    (2019) The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML

    Leukemia 33:2628–2639.

    https://doi.org/10.1038/s41375-019-0581-y

    • PubMed
    • Google Scholar
30. 1. Kang Y-A
    2. Sanalkumar R
    3. O’Geen H
    4. Linnemann AK
    5. Chang C-J
    6. Bouhassira EE
    7. Farnham PJ
    8. Keles S
    9. Bresnick EH

    (2012) Autophagy driven by a master regulator of hematopoiesis

    Molecular and Cellular Biology 32:226–239.

    https://doi.org/10.1128/MCB.06166-11

    • PubMed
    • Google Scholar
31. 1. Kendek A
    2. Sandron A
    3. Lambooij JP
    4. Colmenares SU
    5. Pociunaite SM
    6. Gooijers I
    7. de Groot L
    8. Karpen GH
    9. Janssen A

    (2024) DNA double-strand break movement in heterochromatin depends on the histone acetyltransferase dGcn5

    Nucleic Acids Research 52:11753–11767.

    https://doi.org/10.1093/nar/gkae775

    • PubMed
    • Google Scholar
32. 1. Khadilkar RJ
    2. Rodrigues D
    3. Mote RD
    4. Sinha AR
    5. Kulkarni V
    6. Magadi SS
    7. Inamdar MS

    (2014) ARF1-GTP regulates Asrij to provide endocytic control of Drosophila blood cell homeostasis

    PNAS 111:4898–4903.

    https://doi.org/10.1073/pnas.1303559111

    • PubMed
    • Google Scholar
33. 1. Khadilkar RJ
    2. Vogl W
    3. Goodwin K
    4. Tanentzapf G

    (2017) Modulation of occluding junctions alters the hematopoietic niche to trigger immune activation

    eLife 6:e28081.

    https://doi.org/10.7554/eLife.28081

    • PubMed
    • Google Scholar
34. 1. Khadilkar RJ
    2. Tanentzapf G

    (2019) Septate junction components control Drosophila hematopoiesis through the hippo pathway

    Development 146:dev166819.

    https://doi.org/10.1242/dev.166819

    • PubMed
    • Google Scholar
35. 1. Khadilkar RJ
    2. Ho KYL
    3. Venkatesh B
    4. Tanentzapf G

    (2020) Integrins modulate extracellular matrix organization to control cell signaling during hematopoiesis

    Current Biology 30:3316–3329.

    https://doi.org/10.1016/j.cub.2020.06.027

    • PubMed
    • Google Scholar
36. 1. Kharrat B
    2. Csordás G
    3. Honti V

    (2022) Peeling back the layers of lymph gland structure and regulation

    International Journal of Molecular Sciences 23:7767.

    https://doi.org/10.3390/ijms23147767

    • PubMed
    • Google Scholar
37. 1. Kim J
    2. Kundu M
    3. Viollet B
    4. Guan KL

    (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

    Nature Cell Biology 13:132–141.

    https://doi.org/10.1038/ncb2152

    • PubMed
    • Google Scholar
38. 1. Kollenstart L
    2. de Groot AJL
    3. Janssen GMC
    4. Cheng X
    5. Vreeken K
    6. Martino F
    7. Côté J
    8. van Veelen PA
    9. van Attikum H

    (2019) Gcn5 and Esa1 function as histone crotonyltransferases to regulate crotonylation-dependent transcription

    The Journal of Biological Chemistry 294:20122–20134.

    https://doi.org/10.1074/jbc.RA119.010302

    • PubMed
    • Google Scholar
39. 1. Koschade SE
    2. Brandts CH

    (2020) Selective autophagy in normal and malignant hematopoiesis

    Journal of Molecular Biology 432:261–282.

    https://doi.org/10.1016/j.jmb.2019.06.025

    • PubMed
    • Google Scholar
40. 1. Krzemień J
    2. Dubois L
    3. Makki R
    4. Meister M
    5. Vincent A
    6. Crozatier M

    (2007) Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre

    Nature 446:325–328.

    https://doi.org/10.1038/nature05650

    • PubMed
    • Google Scholar
41. 1. Kuo YM
    2. Andrews AJ

    (2013) Quantitating the specificity and selectivity of Gcn5-mediated acetylation of histone H3

    PLOS ONE 8:e54896.

    https://doi.org/10.1371/journal.pone.0054896

    • PubMed
    • Google Scholar
42. 1. Laboucarié T
    2. Detilleux D
    3. Rodriguez-Mias RA
    4. Faux C
    5. Romeo Y
    6. Franz-Wachtel M
    7. Krug K
    8. Maček B
    9. Villén J
    10. Petersen J
    11. Helmlinger D

    (2017) TORC1 and TORC2 converge to regulate the SAGA co-activator in response to nutrient availability

    EMBO Reports 18:2197–2218.

    https://doi.org/10.15252/embr.201744942

    • PubMed
    • Google Scholar
43. 1. Lerin C
    2. Rodgers JT
    3. Kalume DE
    4. Kim S
    5. Pandey A
    6. Puigserver P

    (2006) GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha

    Cell Metabolism 3:429–438.

    https://doi.org/10.1016/j.cmet.2006.04.013

    • PubMed
    • Google Scholar
44. 1. Liu F
    2. Lee JY
    3. Wei H
    4. Tanabe O
    5. Engel JD
    6. Morrison SJ
    7. Guan JL

    (2010) FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells

    Blood 116:4806–4814.

    https://doi.org/10.1182/blood-2010-06-288589

    • PubMed
    • Google Scholar
45. 1. Liu K
    2. Zhang Q
    3. Lan H
    4. Wang L
    5. Mou P
    6. Shao W
    7. Liu D
    8. Yang W
    9. Lin Z
    10. Lin Q
    11. Ji T

    (2015) GCN5 potentiates glioma proliferation and invasion via STAT3 and AKT signaling pathways

    International Journal of Molecular Sciences 16:21897–21910.

    https://doi.org/10.3390/ijms160921897

    • PubMed
    • Google Scholar
46. 1. Liu T
    2. Wang Q
    3. Li W
    4. Mao F
    5. Yue S
    6. Liu S
    7. Liu X
    8. Xiao S
    9. Xia L

    (2017) Gcn5 determines the fate of Drosophila germline stem cells through degradation of cyclin A

    FASEB Journal 31:2185–2194.

    https://doi.org/10.1096/fj.201601217R

    • PubMed
    • Google Scholar
47. 1. Lu G
    2. Wang Y
    3. Shi Y
    4. Zhang Z
    5. Huang C
    6. He W
    7. Wang C
    8. Shen H-M

    (2022) Autophagy in health and disease: From molecular mechanisms to therapeutic target

    MedComm 3:e150.

    https://doi.org/10.1002/mco2.150

    • PubMed
    • Google Scholar
48. 1. Majaz S
    2. Tong Z
    3. Peng K
    4. Wang W
    5. Ren W
    6. Li M
    7. Liu K
    8. Mo P
    9. Li W
    10. Yu C

    (2016) Histone acetyl transferase GCN5 promotes human hepatocellular carcinoma progression by enhancing AIB1 expression

    Cell & Bioscience 6:47.

    https://doi.org/10.1186/s13578-016-0114-6

    • PubMed
    • Google Scholar
49. 1. Mandal L
    2. Martinez-Agosto JA
    3. Evans CJ
    4. Hartenstein V
    5. Banerjee U

    (2007) A Hedgehog- and Antennapedia-dependent niche maintains Drosophila haematopoietic precursors

    Nature 446:320–324.

    https://doi.org/10.1038/nature05585

    • PubMed
    • Google Scholar
50. 1. Martina JA
    2. Chen Y
    3. Gucek M
    4. Puertollano R

    (2012) MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB

    Autophagy 8:903–914.

    https://doi.org/10.4161/auto.19653

    • PubMed
    • Google Scholar
51. 1. McLeod CJ
    2. Wang L
    3. Wong C
    4. Jones DL

    (2010) Stem cell dynamics in response to nutrient availability

    Current Biology 20:2100–2105.

    https://doi.org/10.1016/j.cub.2010.10.038

    • PubMed
    • Google Scholar
52. 1. Mortensen M
    2. Soilleux EJ
    3. Djordjevic G
    4. Tripp R
    5. Lutteropp M
    6. Sadighi-Akha E
    7. Stranks AJ
    8. Glanville J
    9. Knight S
    10. Jacobsen S-EW
    11. Kranc KR
    12. Simon AK

    (2011) The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance

    The Journal of Experimental Medicine 208:455–467.

    https://doi.org/10.1084/jem.20101145

    • PubMed
    • Google Scholar
53. 1. Mustachio LM
    2. Roszik J
    3. Farria AT
    4. Guerra K
    5. Dent SY

    (2019)

    Repression of GCN5 expression or activity attenuates c-MYC expression in non-small cell lung cancer

    American Journal of Cancer Research 9:1830–1845.

    • PubMed
    • Google Scholar
54. 1. Mutlu B
    2. Puigserver P

    (2021) GCN5 acetyltransferase in cellular energetic and metabolic processes

    Biochimica et Biophysica Acta. Gene Regulatory Mechanisms 1864:194626.

    https://doi.org/10.1016/j.bbagrm.2020.194626

    • PubMed
    • Google Scholar
55. 1. Nagy Z
    2. Tora L

    (2007) Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation

    Oncogene 26:5341–5357.

    https://doi.org/10.1038/sj.onc.1210604

    • PubMed
    • Google Scholar
56. 1. Napolitano G
    2. Esposito A
    3. Choi H
    4. Matarese M
    5. Benedetti V
    6. Di Malta C
    7. Monfregola J
    8. Medina DL
    9. Lippincott-Schwartz J
    10. Ballabio A

    (2018) mTOR-dependent phosphorylation controls TFEB nuclear export

    Nature Communications 9:3312.

    https://doi.org/10.1038/s41467-018-05862-6

    • PubMed
    • Google Scholar
57. 1. Pearson KJ
    2. Baur JA
    3. Lewis KN
    4. Peshkin L
    5. Price NL
    6. Labinskyy N
    7. Swindell WR
    8. Kamara D
    9. Minor RK
    10. Perez E
    11. Jamieson HA
    12. Zhang Y
    13. Dunn SR
    14. Sharma K
    15. Pleshko N
    16. Woollett LA
    17. Csiszar A
    18. Ikeno Y
    19. Le Couteur D
    20. Elliott PJ
    21. Becker KG
    22. Navas P
    23. Ingram DK
    24. Wolf NS
    25. Ungvari Z
    26. Sinclair DA
    27. de Cabo R

    (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span

    Cell Metabolism 8:157–168.

    https://doi.org/10.1016/j.cmet.2008.06.011

    • PubMed
    • Google Scholar
58. 1. Pennetier D
    2. Oyallon J
    3. Morin-Poulard I
    4. Dejean S
    5. Vincent A
    6. Crozatier M

    (2012) Size control of the Drosophila hematopoietic niche by bone morphogenetic protein signaling reveals parallels with mammals

    PNAS 109:3389–3394.

    https://doi.org/10.1073/pnas.1109407109

    • Google Scholar
59. 1. Qin B
    2. Yu S
    3. Chen Q
    4. Jin LH

    (2023) Atg2 regulates cellular and humoral immunity in Drosophila

    Insects 14:706.

    https://doi.org/10.3390/insects14080706

    • PubMed
    • Google Scholar
60. 1. Rabanal-Ruiz Y
    2. Otten EG
    3. Korolchuk VI

    (2017) mTORC1 as the main gateway to autophagy

    Essays in Biochemistry 61:565–584.

    https://doi.org/10.1042/EBC20170027

    • PubMed
    • Google Scholar
61. 1. Raser JM
    2. O’Shea EK

    (2004) Control of stochasticity in eukaryotic gene expression

    Science 304:1811–1814.

    https://doi.org/10.1126/science.1098641

    • PubMed
    • Google Scholar
62. 1. Riffelmacher T
    2. Simon A-K

    (2017) Mechanistic roles of autophagy in hematopoietic differentiation

    The FEBS Journal 284:1008–1020.

    https://doi.org/10.1111/febs.13962

    • PubMed
    • Google Scholar
63. 1. Salunkhe S
    2. Mishra SV
    3. Nair J
    4. Ghosh S
    5. Choudhary N
    6. Kaur E
    7. Shah S
    8. Patkar K
    9. Anand D
    10. Khattry N
    11. Hasan SK
    12. Dutt S

    (2018) Inhibition of novel GCN5-ATM axis restricts the onset of acquired drug resistance in leukemia

    International Journal of Cancer 142:2175–2185.

    https://doi.org/10.1002/ijc.31242

    • PubMed
    • Google Scholar
64. 1. Schuetz A
    2. Bernstein G
    3. Dong A
    4. Antoshenko T
    5. Wu H
    6. Loppnau P
    7. Bochkarev A
    8. Plotnikov AN

    (2007) Crystal structure of a binary complex between human GCN5 histone acetyltransferase domain and acetyl coenzyme A

    Proteins 68:403–407.

    https://doi.org/10.1002/prot.21407

    • PubMed
    • Google Scholar
65. 1. Shim J
    2. Mukherjee T
    3. Banerjee U

    (2012) Direct sensing of systemic and nutritional signals by haematopoietic progenitors in Drosophila

    Nature Cell Biology 14:394–400.

    https://doi.org/10.1038/ncb2453

    • PubMed
    • Google Scholar
66. 1. Shim J
    2. Gururaja-Rao S
    3. Banerjee U

    (2013) Nutritional regulation of stem and progenitor cells in Drosophila

    Development 140:4647–4656.

    https://doi.org/10.1242/dev.079087

    • PubMed
    • Google Scholar
67. 1. Shravage BV
    2. Hill JH
    3. Powers CM
    4. Wu L
    5. Baehrecke EH

    (2013) Atg6 is required for multiple vesicle trafficking pathways and hematopoiesis in Drosophila

    Development 140:1321–1329.

    https://doi.org/10.1242/dev.089490

    • PubMed
    • Google Scholar
68. 1. Sinenko SA
    2. Mandal L
    3. Martinez-Agosto JA
    4. Banerjee U

    (2009) Dual role of wingless signaling in stem-like hematopoietic precursor maintenance in Drosophila

    Developmental Cell 16:756–763.

    https://doi.org/10.1016/j.devcel.2009.03.003

    • PubMed
    • Google Scholar
69. 1. Sinha A
    2. Khadilkar RJ
    3. Vinay KS
    4. Roychowdhury Sinha A
    5. Inamdar MS

    (2013) Conserved regulation of the JAK/STAT pathway by the endosomal protein asrij maintains stem cell potency

    Cell Reports 4:649–658.

    https://doi.org/10.1016/j.celrep.2013.07.029

    • PubMed
    • Google Scholar
70. 1. Smith ER
    2. Belote JM
    3. Schiltz RL
    4. Yang XJ
    5. Moore PA
    6. Berger SL
    7. Nakatani Y
    8. Allis CD

    (1998) Cloning of Drosophila GCN5: conserved features among metazoan GCN5 family members

    Nucleic Acids Research 26:2948–2954.

    https://doi.org/10.1093/nar/26.12.2948

    • PubMed
    • Google Scholar
71. 1. Song TT
    2. Cai RS
    3. Hu R
    4. Xu YS
    5. Qi BN
    6. Xiong YA

    (2021) The important role of TFEB in autophagy-lysosomal pathway and autophagy-related diseases: a systematic review

    European Review for Medical and Pharmacological Sciences 25:1641–1649.

    https://doi.org/10.26355/eurrev_202102_24875

    • PubMed
    • Google Scholar
72. 1. Sousa-Nunes R
    2. Yee LL
    3. Gould AP

    (2011) Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila

    Nature 471:508–512.

    https://doi.org/10.1038/nature09867

    • PubMed
    • Google Scholar
73. 1. Tiwari SK
    2. Toshniwal AG
    3. Mandal S
    4. Mandal L

    (2020) Fatty acid β-oxidation is required for the differentiation of larval hematopoietic progenitors in Drosophila

    eLife 9:e53247.

    https://doi.org/10.7554/eLife.53247

    • PubMed
    • Google Scholar
74. 1. Tokusumi Y
    2. Tokusumi T
    3. Shoue DA
    4. Schulz RA

    (2012) Gene regulatory networks controlling hematopoietic progenitor niche cell production and differentiation in the Drosophila lymph gland

    PLOS ONE 7:e41604.

    https://doi.org/10.1371/journal.pone.0041604

    • PubMed
    • Google Scholar
75. 1. Tzelepis K
    2. Koike-Yusa H
    3. De Braekeleer E
    4. Li Y
    5. Metzakopian E
    6. Dovey OM
    7. Mupo A
    8. Grinkevich V
    9. Li M
    10. Mazan M
    11. Gozdecka M
    12. Ohnishi S
    13. Cooper J
    14. Patel M
    15. McKerrell T
    16. Chen B
    17. Domingues AF
    18. Gallipoli P
    19. Teichmann S
    20. Ponstingl H
    21. McDermott U
    22. Saez-Rodriguez J
    23. Huntly BJP
    24. Iorio F
    25. Pina C
    26. Vassiliou GS
    27. Yusa K

    (2016) A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia

    Cell Reports 17:1193–1205.

    https://doi.org/10.1016/j.celrep.2016.09.079

    • PubMed
    • Google Scholar
76. 1. Wang L
    2. Mizzen C
    3. Ying C
    4. Candau R
    5. Barlev N
    6. Brownell J
    7. Allis CD
    8. Berger SL

    (1997) Histone acetyltransferase activity is conserved between yeast and human GCN5 and is required for complementation of growth and transcriptional activation

    Molecular and Cellular Biology 17:519–527.

    https://doi.org/10.1128/MCB.17.1.519

    • PubMed
    • Google Scholar
77. 1. Wang Y
    2. Guo YR
    3. Liu K
    4. Yin Z
    5. Liu R
    6. Xia Y
    7. Tan L
    8. Yang P
    9. Lee J-H
    10. Li X
    11. Hawke D
    12. Zheng Y
    13. Qian X
    14. Lyu J
    15. He J
    16. Xing D
    17. Tao YJ
    18. Lu Z

    (2017) KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase

    Nature 552:273–277.

    https://doi.org/10.1038/nature25003

    • Google Scholar
78. 1. Wang Y
    2. Huang Y
    3. Liu J
    4. Zhang J
    5. Xu M
    6. You Z
    7. Peng C
    8. Gong Z
    9. Liu W

    (2020) Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

    EMBO Reports 21:e48335.

    https://doi.org/10.15252/embr.201948335

    • PubMed
    • Google Scholar
79. 1. Warr MR
    2. Binnewies M
    3. Flach J
    4. Reynaud D
    5. Garg T
    6. Malhotra R
    7. Debnath J
    8. Passegué E

    (2013) FOXO3A directs a protective autophagy program in haematopoietic stem cells

    Nature 494:323–327.

    https://doi.org/10.1038/nature11895

    • PubMed
    • Google Scholar
80. 1. Woo AJ
    2. Kim J
    3. Xu J
    4. Huang H
    5. Cantor AB

    (2011) Role of ZBP-89 in human globin gene regulation and erythroid differentiation

    Blood 118:3684–3693.

    https://doi.org/10.1182/blood-2011-03-341446

    • PubMed
    • Google Scholar
81. 1. Wu Y
    2. Ma S
    3. Xia Y
    4. Lu Y
    5. Xiao S
    6. Cao Y
    7. Zhuang S
    8. Tan X
    9. Fu Q
    10. Xie L
    11. Li Z
    12. Yuan Z

    (2017) Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim

    Cell Death & Disease 8:e2570.

    https://doi.org/10.1038/cddis.2016.465

    • PubMed
    • Google Scholar
82. 1. Zhao M
    2. Geng R
    3. Guo X
    4. Yuan R
    5. Zhou X
    6. Zhong Y
    7. Huo Y
    8. Zhou M
    9. Shen Q
    10. Li Y
    11. Zhu W
    12. Wang J

    (2017) PCAF/GCN5-mediated acetylation of RPA1 promotes nucleotide excision repair

    Cell Reports 20:1997–2009.

    https://doi.org/10.1016/j.celrep.2017.08.015

    • PubMed
    • Google Scholar

Author details

1. Arjun Aji Reeja

   1. Stem Cell and Tissue Homeostasis Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
   2. Champalimaud Research, Champalimaud Foundation, Lisboa, Portugal

   Contribution

   Resources, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Mincy Kunjumon

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1127-4491

2. Mincy Kunjumon

   1. Stem Cell and Tissue Homeostasis Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
   2. Homi Bhabha National Institute, Training School Complex, Mumbai, India

   Contribution

   Resources, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Arjun Aji Reeja

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0001-5667-0586

3. Suraj Math

   1. Stem Cell and Tissue Homeostasis Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
   2. Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States

   Contribution

   Validation, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Laxmi Kata

   Stem Cell and Tissue Homeostasis Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India

   Contribution

   Validation, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

5. Rohan Jayant Khadilkar

   1. Stem Cell and Tissue Homeostasis Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
   2. Homi Bhabha National Institute, Training School Complex, Mumbai, India

   Contribution

   Conceptualization, Resources, Data curation, Funding acquisition, Visualization, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   rkhadilkar@actrec.gov.in

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7297-2736

• 3,291

  views

• 167

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.