Amino-terminal acetylation is one of the most common protein modifications, occurring co- and post-translationally. Approximately 80% of cytosolic proteins are amino-terminally acetylated in humans and ~50% in yeast (Arnesen et al., 2009), while amino-terminal acetylation is less common in prokaryotes and archaea (Dörfel and Lyon, 2015). Amino-terminal acetylation is catalyzed by a set of enzymes, the N-terminal acetyltransferases (NATs), which transfer an acetyl group from acetyl-coenzyme A (Ac-CoA) to the free α-amino group of a protein’s N-terminus. To date, eight distinct NATs (NatA–NatH) have been identified in eukaryotes that are classified based on different subunit compositions and substrate specificities (Polevoda et al., 2009; Aksnes et al., 2019; Starheim et al., 2012). Amino-terminal acetylation has been implicated in steering protein folding, stability or degradation, subcellular targeting, and complex formation (Ree et al., 2018; Shemorry et al., 2013; Dikiy and Eliezer, 2014; Holmes et al., 2014; Scott et al., 2011). The vital role of NATs and amino-terminal acetylation in development has also emerged (Lee et al., 2018).

NatA, the major NAT complex, targets ~40% of the human proteome, acetylating Ser-, Ala-, Gly-, Thr-, Val-, and Cys N-termini after removal of the initiator methionine (Arnesen et al., 2009; Starheim et al., 2012). Human NatA consists of two main subunits, the catalytic subunit N-α-acetyltransferase 10 (NAA10) (Ard1) and the auxiliary subunit NAA15 (Nat1), and a regulatory subunit HYPK (Arnesen et al., 2005; Arnesen et al., 2010; Gottlieb and Marmorstein, 2018). NAA15 function has been linked to cell survival, tumor progression, and retinal development (Arnesen et al., 2006a; Gendron et al., 2010). In addition, Naa10-catalyzed N-terminal acetylation has been reported to be essential for development in many species (Lee et al., 2018; Wang et al., 2010; Chen et al., 2014; Linster et al., 2015; Ree et al., 2015; Feng et al., 2016; Chen et al., 2018), and although NatA is not essential in Saccharomyces cerevisiae, depletion of Naa10 or Naa15 has strong effects, including slow growth and decreased survival when exposed to various stresses (Mullen et al., 1989; Polevoda and Sherman, 2003).

NAA10 mutations were found to be associated with several human diseases characterized by severe phenotypes, including global developmental defects (Lee et al., 2018). Among these, the X-linked Ogden syndrome (OS) (Myklebust et al., 2015; Rope et al., 2011) shows the most severe pathological features such as infant lethality and has reduced NatA catalytic activity. In a S. cerevisiae model for the Naa10 Ser37Pro mutant, the mutation impairs NatA complex formation and leads to a reduction in NatA catalytic activity and functionality (Van Damme et al., 2014; Dörfel et al., 2017). Further, OS patient-derived cells have impaired amino-terminal acetylation in vivo of some NatA substrates (Myklebust et al., 2015). Over the years, many additional pathogenic NAA10 variants have been identified in NAA10 or NAA15 (Esmailpour et al., 2014; Popp et al., 2015; Casey et al., 2015; McTiernan et al., 2018; Ree et al., 2019; Støve et al., 2018; Cheng et al., 2019; Cheng et al., 2018; Johnston et al., 2019) and the collection of presenting symptoms for families with NAA10 mutations is currently referred to as Ogden syndrome or NAA10-related syndrome (Wu and Lyon, 2018).

The autosomal NAA10 homolog, NAA11 (ARD2), has been reported to be present in mice and humans, and is co-expressed with NAA10 in human cell lines (Arnesen et al., 2006b). Therefore, NAA11 could conceivably compensate when NAA10 is reduced or lacking (Lee et al., 2018). However, NAA11 was only found in testis and placenta in human and gonadal tissues in mouse, while NAA10 showed widespread expression in various tissues in embryos and adults (Pang et al., 2011). Thus, any functional redundancy or compensation might be limited to certain tissues only.

To elucidate the functional role of Naa10 during development in mice, we used two different Naa10-deficient mouse lines: one, referred to as Naa10 knockout (KO), which was previously reported specifically related to bone density in postnatal day 3 (P3) mice (Yoon et al., 2014), and another denoted as Naa10^{tm1a(EUCOMM)Hmgu} (Naa10^tm1a), generated in this study. These Naa10-deficient mice exhibit pleiotropic developmental abnormalities at a range of different ages, overlapping with some of the phenotypes seen in human disease involving NAA10 impairment. Because we did not discover major changes in the overall Nt-acetylome in Naa10 KO mice, we hypothesized that there might be a compensating gene in mice, which led us to the identification of a new paralog of Naa10, which we name Naa12. Naa12 is expressed in several organs (liver, kidney, heart, and testis) and, like Naa10, binds to Naa15 to mediate NatA activity. Furthermore, lethality was observed in Naa10 Naa12 double-KO mice, which supports the compensatory role of Naa12 in vivo. Thus, we demonstrate that Naa10 is essential for proper development and Naa12, a newly identified paralog of Naa10, can play a compensatory role in mice.

We have shown that Naa10 deficiency results in pleotropic developmental defects in two different Naa10-deficient mouse models. Similar to infant mortality in some OS males, the lethality of Naa10 KO mice increased dramatically in pups in the first three days of life (Figure 1B). Defects in kidney, brain, pigmentation (piebaldism), and ribs were observed during embryonic or early postnatal stages in some mice (Figure 2B, C). These observed phenotypes overlap with some of the phenotypes found in surviving humans with OS, including supernumerary vertebrae and hydrocephaly, although piebaldism has not been reported to date in any humans. However, the puzzling lack of embryonic lethality in the Naa10 KO mice prompted us to discover Naa12 as a possible compensatory NAT, with Naa10-like amino-terminal acetylation activity (Figure 4A), with an interaction between Naa15 and Naa12 (Figure 4B), and with enzymatic activity in a chimeric complex with human NAA15 (Figure 4C). In addition, co-immunoprecipitation of endogenous Naa15 from Naa10 KO mouse tissues followed by mass spectrometry analysis (Table 2) and amino-terminal acetylation assays (Figure 3C) fully supports that the endogenous Naa12-Naa15 complexes produces NatA activity. Finally, we found genetic proof of the compensatory activity of Naa12 in mice when we observed embryonic lethality in in Naa10 Naa12 DKO male and Naa10^+/- Naa12^-/- female mice (Figure 6). This compensation by Naa12 explains the mouse proteomics data indicating normal amino-terminal acetylation in Naa10 KO mice (Figure 3A). We have confirmed the expression of Naa12 in various tissues using qPCR (Figure 4—figure supplement 1A).

Gene duplication has long been believed to be a major driving force in evolution that provides genetic novelty in organisms. Paralogous genes, originating by small-scale or whole-genome duplication, overlap functional roles for each other and can completely or partially compensate for the loss of the duplicate gene (Peng, 2019; Veitia, 2017). There is not yet any human reported with complete KO for NAA10. There is one published truncating variant in the C-terminal portion of NAA10 in a male patient with microphthalmia (Cheng et al., 2019), but unfortunately there are no cell lines available from this family to confirm whether any truncated NAA10 protein is expressed, as was shown with a splice-site mutation in a Lenz microphthalmia family (Esmailpour et al., 2014). NAA10 was also identified in screens for essential genes in human cell lines (Blomen et al., 2015; Wang et al., 2015), so it seems unlikely that an unknown NAA10-like paralogous gene exists in humans, other than the already known NAA11.

The pleiotropic phenotypes shown in Naa10 KO mice, including hypopigmentation and supernumerary ribs with a penetrance of 100%, were not observed in the Naa12 KO mice. Naa10 itself has been described to have N-ɛ-acetyl-activity towards internal lysine residues of proteins involved in various disease- and development-related signaling pathways (Lee et al., 2018), although its acetylation of some substrates is controversial (Magin et al., 2016; Vo, 2020). Since the Nt-acetylome appears to be globally intact in MEFs from Naa10 KO mice (Figure 3A), it is possible that the presented phenotypes could be due to the loss of Naa10-specific N-ɛ-acetyl-activity or non-catalytic roles of Naa10 (Aksnes et al., 2019). Alternatively, the quantitative expression of Naa10 and Naa12 might be different within or between tissues, which might then explain why there is clearly a phenotype for Naa10^+/- Naa12^+/- female mice (not born at Mendelian ratios and the few that are born are usually much smaller) but no apparent phenotype in Naa10^+/+ Naa12^-/- female mice. It seems likely that the mechanism cannot be simply additive between two equally expressed proteins, because if the expression of each protein is theoretically set at an arbitrary unit of 10, then Naa10^+/- Naa12^+/- female mice might possibly have half as much of each protein, so that the total dose of both proteins together would be 10, instead of 20. Likewise, the total dose of both proteins together would also be predicted to be 10 in a Naa10^+/+ Naa12^-/- female. Yet, the Naa10^+/- Naa12^+/- female mice have a phenotype, whereas the Naa10^+/+ Naa12^-/- female mice do not (Figure 6). Therefore, other explanations could include different tissue-specific dosages of each protein, different expression between different tissues, possible X-chromosome skewing for the X-linked Naa10 in different tissues, or different functions of the two enzymes, including Naa10-specific N-ɛ-acetyl-activity or non-catalytic roles of Naa10 (Aksnes et al., 2019). These questions remain unanswered and are worth exploring in future studies. It is worth highlighting that X-chromosome inactivation could certainly be one explanation, given that males that are Naa10^+/Y with Naa12^+/- or Naa12^-/- show expected survival rates, whereas females that are Naa10^+/- with Naa12^+/- show ~35% survival but with Naa12^-/- show 0% survival (Table 4).

There are several clinical features that were presented in the original description of OS (Rope et al., 2011) which can now be better understood in light of the phenotypes found in the KO mouse model. For example, all of the affected children in the first families with OS were noted to have large and, in some cases, persistently open fontanels (Myklebust et al., 2015; Rope et al., 2011). For one child (family 1, individual II-1), CT scanning revealed cerebral atrophy with enlarged ventricles, and in another child (family 1, individual III-4), there was evidence on magnetic resonance imaging (MRI) of ‘moderate lateral and third ventricular dilatation without identified cause.’ Lastly, all of the children had respiratory depression and apneic episodes, along with varying course of hypotonia and/or hypertonia (including documented hyperreflexia in at least one case [family 2, individual III-2]). In retrospect, it seems that these clinical features could be consistent with mild hydrocephaly in these probands with OS, which resolved over time. This is also consistent with the ventriculomegaly reported in several female OS probands with missense mutations in NAA10, along with ventriculomegaly in one other male proband who died in the first week of life, with generalized hypotonia and lack of spontaneous respirations (Saunier et al., 2016). One of the female patients with an Arg83Cys mutation in Naa10 (#9 in Table 1 of that paper) was reported as having intraventricular hemorrhage in the occipital horn, hypoxic-ischemic encephalopathy, and a ventriculo-peritoneal shunt. It is possible that this sequence of events is compatible with hydrocephaly with clinical signs and symptoms that required the placement of the shunt.

There are additional cardiac and skeletal features that are also worth re-examining in light of these new findings. In some of the original cases of OS, there were varying levels of pulmonary valve stenosis detected on echocardiography, along with some documentation of pulmonary hypoplasia (Rope et al., 2011). For example, individual III-7 in family 1 was found on echocardiography to have small persistent ductus arteriosus, a mildly decreased left ventricular systolic function, an abnormal appearing aortic valve, an enlargement of the right ventricle, decreased right ventricular systolic function, and persistence of the foramen ovale. Individual III-6 from this same extended family was found on echocardiography to have a thickened bicuspid aortic valve and mild pulmonary hypertension. One of the OS female patients with an Arg83Cys mutation in NAA10 was reported to have ‘supernumerary vertebrae’ (Saunier et al., 2016). Prompted by our findings of supernumerary ribs in the mice, we obtained an MRI report for this patient, in which the radiologist concluded that there appeared to be 25 distinct vertebrae, as opposed to the usual 24, with a suggestion of a 13th rib, at least on the right. The report went on to state that “the vertebrae represent seven cervical vertebrae, 13 rib-bearing thoracic vertebrae, and five lumbar vertebrae, and the L1 vertebra is mildly dysmorphic, with a suggestion of anterior breaking.” In addition, chest and abdominal X-rays from two of the brothers in generation VI of a family with microphthalmia demonstrated the presence of 13 rib-bearing thoracic vertebrae, alongside the dramatic scoliosis in both individuals. Four other females carrying mutations in Naa10 were reported as having either pectus carinatum or excavatum (Saunier et al., 2016), one of the boys with OS (family 1, individual III-4) was noted to have pectus excavatum, and retrospective review of some of the clinical photographs appears to show mild pectus excavatum in individual III-6 of the same family. Studies of human populations have shown that the levels of transition may be shifted cephalad, resulting in 23 mobile vertebrae, or shifted caudad, resulting in 25 presacral vertebrae. Such variations may occur in 2–11% of the population (Bornstein and Peterson, 1966). In addition, the number of ribs can also vary in mice as a result of teratogenic and genetic influences (Mclaren and Michie, 1958; Chernoff and Rogers, 2004). However, the complete penetrance for supernumerary ribs in the Naa10-deficient mice, along with the presence of extras ribs in some of the patients, suggests that there is a pathway common to humans and mice that is altered by mutations involving NAA10.

Several mouse mutants show similar cardiac or skeletal phenotypes to the Naa10-deficient mice. Pax3 mutants phenocopy our Naa10^-/- mutants as Pax3^+/- adults exhibit 100% piebaldism and exhibit neural crest (NC)-related PTA/DORV with concomitant VSDs (Conway et al., 1997a; Conway et al., 1997b; van den Hoff and Moorman, 2000; Olaopa et al., 2011). Pax3 systemic nulls also have skeletal defects due to abnormal somite morphogenesis (Henderson et al., 1999; Dickman et al., 1999). Moreover, Pax3 cKOs demonstrated that NC-specific deletion is sufficient to cause DORV/VSDs and death at birth (Olaopa et al., 2011; Koushik et al., 2002), and that restricted deletion within the neuroepithelium causes congenital hydrocephalus (Zhou and Conway, 2016). While Pax7 systemic deletion does not cause NC-associated defects, it does exhibit overlapping expression, and Pax3-Pax7 compound heterozygous mice develop hydrocephalus (Zhou and Conway, 2016), suggesting combinatorial function. Hox C8^-/- mice exhibit an extra rib and an extra rib articulating with the sternum (Le Mouellic et al., 1992; Juan and Ruddle, 2003), and an unfused sacral vertebra, which lead to 27 presacral vertebrae (van den Akker et al., 2001), as seen in our model. Hox A4^-/- mice described in Horan et al., 1994 show cervical fusions of C2/C3, a rib on C7 not fully penetrant and sternal defects with bone ossification anomalies. Hox A5^-/- mice display numerous cervico-thoracic defects such as a rib process coming from the seventh cervical vertebra, an increase in the number of sternebrae and total number of ribs (Jeannotte et al., 1993). Both Hox A4^-/- and A5^-/- mice exhibit an extra rib articulating with the sternum. Hox D3^-/- mice are the only Hox gene mutation leading to cervical fusion of both the atlas and axis (Condie and Capecchi, 1993). Hox A9^-/- mice have anteriorization of both sacral and lumbar parts, with an extra pair of ribs at the lumbar level. Hox A9^-/- mice do not have any relevant sternal defect (Fromental-Ramain et al., 1996). Hox B9^-/- mice have an extra rib articulating with the sternum and 14 pairs of rib (Chen and Capecchi, 1997). These phenotypes, especially Hox C8, share common features with the Naa10-deficient mice. This phenotype is also close to the Rpl38^-/- phenotype (Kondrashov et al., 2011), except for the sacral fusion described in Rpl38^-/- mice. Interestingly, it was shown that Hox genes were dysregulated in this genotype. The skeletal findings and comparison to other mutant mice suggest a pattern consistent with a homeotic anterior transformation hypothesis.

The developmental role of Naa10 in mice has been previously described (Lee et al., 2017). Lee et al. reported embryonic lethality at E12.5–14.5 and beyond (due to placental defects), hydrocephaly, postnatal growth retardation, and maternal effect lethality in Naa10 KO mice and suggested that genomic imprinting dysregulation is associated with those developmental phenotypes. In the present study, hydrocephaly and postnatal growth retardation were also apparent, but embryonic lethality was not observed, which prompted the search for and discovery of Naa12. The previous paper (Lee et al., 2017) did not report the piebaldism, homeotic anterior transformation, hydronephrosis, and genital defects (such as seminal vesicle malformation and hydrometrocolpos), nor did it explain the cause of death in the first day of life, which is at least partly due to congenital heart defects, as reported herein. A more recent paper from the same group reported that conventional and adipose-specific Naa10p deletions in mice resulted in increased energy expenditure, thermogenesis, and beige adipocyte differentiation in the surviving mice (Lee et al., 2019), although the authors do not comment on whether any of the male mice used in that study starting at age 5 weeks ended up developing hydrocephaly and/or hydronephrosis, which we have observed in older mice. Although the Lee et al., 2017 paper reported a very high maternal effect lethality rate of 90% (46/51) (otherwise stated as a survival rate of 10% [5/51]) for newborns in matings following Naa10^-/- female and C57BL/6J WT male intercrossing, this rate was only 29% (37/127) in this same mating herein in the first 24 hr of life and with a total death rate in the first three days for all newborns of 46/127, or 36% (Supplementary file 1d), with this result deriving from a larger number of mating pairs, litters, and pups. Although this rate of 36% is higher than that seen with matings involving Naa10^+/- females (15.8% and 13.6%) (Supplementary file 1d), the explanation for this ~20% difference in survival in the first three days of life could involve differences in maternal care provided by the Naa10^+/- and Naa10^-/- females, but this would have to be investigated in future studies, involving detailed behavioral and cognitive assessment of the dams.

The reasons for the differences between the studies in regards to maternal effect lethality and in utero lethality are unknown at present. Whilst Lee et al. deleted Naa10 exons 2–6 (Lee et al., 2017), the current study deleted Naa10 exons 1–4 or used an allele Naa10^tm1a expressing β-galactosidase instead of the Naa10 gene (Figure 1—figure supplement 1D), and there was not any significant embryonic lethality in either line (Supplementary file 1a, b). All three of these mouse models were made using 129Sv/Ev ES cells, and all three are nulls lacking Naa10 protein. It is the case that the previous study used the Cre/loxP system to generate the Naa10 KO mice, where a floxed Naa10 female mouse was crossed with the Ella-Cre transgenic male mouse expressing Cre recombinase for germ line deletion of loxP-flanked Naa10, whereas our mice were made using standard gene-targeting methods without the use of Cre recombinase, but it is not clear how this would have resulted in embryonic lethality, particularly as these mice were only used after ‘at least six generations of backcross with C57BL/6 mice,’ which are noted by the authors to be the substrain C57BL/6JNarl, first established at the Animal Center of National Research Institute from the Jackson Laboratory (JAX) in 1995. The explanation for differences in embryonic lethality might be more likely due to different combinations of modifying alleles that are present in the different C57BL/6J substrain genetic backgrounds, rather than differences in our model systems, and future plans will address this after back-crossing more than 20 generations to C57BL/6J (imported annually from JAX) to achieve an entirely inbred line. The impact of genetic background is supported by the observation that additional null alleles on mixed genetic backgrounds, made during the process of generating missense mouse models for OS, have far less penetrance for a range of the various phenotypes, including much less perinatal lethality (unpublished observations).

In conclusion, our study provides strong evidence that Naa10, the catalytic subunit of NatA, is critical for normal development in mice. Furthermore, this study explains the puzzle regarding the lack of complete embryonic lethality in the Naa10 KO mice due to the discovery of a second mouse Naa10 paralog, which, unlike Naa11, is expressed in the heart as well as other tissues. Taken together, our findings suggest that the newly identified Naa12 can functionally rescue Naa10 loss and act as a catalytic subunit in mouse NatA complexes.

All data generated or analysed during this study are included in the manuscript and supporting files. Mass spectrometry data were uploaded to PRIDE under Project Name: Naa10 mutant mouse N-terminome LC-MS, Project accession: PXD026410 and Project Name: mNaa10-KO liver immunoprecipitation, Project accession: PXD026684.

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Author details

1. Hyae Yon Kweon

   Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

   Contribution

   Formal analysis, Investigation, Writing - original draft, Writing - review and editing

   Contributed equally with

   Mi-Ni Lee

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1534-0767

2. Mi-Ni Lee

   1. Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea
   2. Laboratory Animal Resource Center Korea ResearchInstitute of Bioscience and Biotechnology, Chungbuk, Republic of Korea

   Present address

   Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea

   Contribution

   Supervision, Investigation, Project administration, Writing - review and editing

   Contributed equally with

   Hyae Yon Kweon

   For correspondence

   minilee@kribb.re.kr

   Competing interests

   No competing interests declared

3. Max Dorfel

   Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Seungwoon Seo

   Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Leah Gottlieb

   1. Department of Chemistry, University of Pennsylvania, Philadelphia, United States
   2. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

6. Thomas PaPazyan

   Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. Nina McTiernan

   Department of Biomedicine, University of Bergen, Bergen, Norway

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1749-6933

8. Rasmus Ree

   Department of Biomedicine, University of Bergen, Bergen, Norway

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. David Bolton

   Department of Molecular Biology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, United States

   Contribution

   Formal analysis, Writing - review and editing

   Competing interests

   No competing interests declared

10. Andrew Garcia

    Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

11. Michael Flory

    Research Design and Analysis Service, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

12. Jonathan Crain

    Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

13. Alison Sebold

    Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

14. Scott Lyons

    Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

15. Ahmed Ismail

    Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

16. Elaine Marchi

    Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

17. Seong-keun Sonn

    Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

18. Se-Jin Jeong

    Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6375-5334

19. Sejin Jeon

    Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3819-3421

20. Shinyeong Ju

    Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5483-4690

21. Simon J Conway

    Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States

    Contribution

    Investigation

    Competing interests

    No competing interests declared

22. Taesoo Kim

    Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3902-1058

23. Hyun-Seok Kim

    Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

24. Cheolju Lee

    1. Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Republic of Korea
    2. Department of Converging Science and Technology, KHU-KIST, Kyung Hee University, Seoul, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-8482-4696

25. Tae-Young Roh

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5833-0844

26. Thomas Arnesen

    1. Department of Biomedicine, University of Bergen, Bergen, Norway
    2. Department of Biological Sciences, University of Bergen, Bergen, Norway
    3. Department of Surgery, Haukeland University Hospital, Bergen, Norway

    Contribution

    Supervision, Writing - review and editing

    Competing interests

    No competing interests declared

27. Ronen Marmorstein

    1. Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    2. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    3. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

    Contribution

    Supervision, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4373-4752

28. Goo Taeg Oh

    Department of Life Science and College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea

    Contribution

    Funding acquisition, Project administration, Writing - review and editing

    For correspondence

    gootaeg@ewha.ac.kr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1104-1698

29. Gholson J Lyon

    1. Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, United States
    2. Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, United States
    3. Biology PhD Program, The Graduate Center, The City University of New York, New York, United States
    4. George A. Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, United States

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    gholsonjlyon@gmail.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-5869-0716

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