TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation
- CMRI, The University of Sydney, Australia
Abstract
Protein interaction is critical molecular regulatory activity underlining cellular functions and precise cell fate choices. Using TWIST1 BioID-proximity-labelling and network propagation analyses, we discovered and characterized a TWIST-chromatin regulatory module (TWIST1-CRM) in the neural crest cells (NCC). Combinatorial perturbation of core members of TWIST1-CRM: TWIST1, CHD7, CHD8, and WHSC1 in cell models and mouse embryos revealed that loss of the function of the regulatory module resulted in abnormal differentiation of NCCs and compromised craniofacial tissue patterning. Following NCC delamination, low level of TWIST1-CRM activity is instrumental to stabilize the early NCC signatures and migratory potential by repressing the neural stem cell programs. High level of TWIST1 module activity at later phases commits the cells to the ectomesenchyme. Our study further revealed the functional interdependency of TWIST1 and potential neurocristopathy factors in NCC development.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Sequencing data have been deposited in GEO under accession codes GSE130251. External data analyzed has been listed in Supplementary File 6.
-
TWIST1 direct targets during embryonic stem cell differentiation [ChIP-seq]NCBI Gene Expression Omnibus, GSE130251.
-
Dissecting neural differentiation regulatory networks through epigenetic footprintingNCBI Gene Expression Omnibus, GSE62193.
-
AF22_H3K36me3NCBI Gene Expression Omnibus, GSM2902410.
-
Genome-wide maps of chromatin state during the differentiation of hESC into hNECs (ChIP-Seq)NCBI Gene Expression Omnibus, GSM1973975.
-
Transcription factors interfering with dedifferentiation induce direct conversionNCBI Gene Expression Omnibus, GSM1012189.
-
Selective influence of Sox2 on POU transcription factor binding in embryonic and neural stem cellsNCBI Gene Expression Omnibus, GSM1711445.
-
Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional ProgramsThe European Nucleotide Archive, ERS580651.
-
Spatio-temporal structure of cell fate decisions in murine neural crestNCBI Gene Expression Omnibus, GSE129114.
Article and author information
Author details
Funding
National Health and Medical Research Council (1066832,1079160,1003100,1110751)
- Mark E Graham
- Patrick PL Tam
Australian Research Council (1094008)
- Xiaochen Fan
- Patrick PL Tam
University of Sydney
- Xiaochen Fan
Children's Medical Research Institute
- Xiaochen Fan
- Pierre Osteil
- Nicolas Fossat
Carlsbergfondet (CF15-1056,CF16-0066)
- Kasper Engholm-Keller
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentations were performed in compliance with animal ethics and welfare guidelines stipulated by the Children's Medical Research Institute/Children's Hospital at Westmead Animal Ethics Committee, protocol number C230.
Copyright
© 2021, Fan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,184
- views
-
- 508
- downloads
-
- 36
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation
eLife 10:e62873.
https://doi.org/10.7554/eLife.62873
Further reading
-
- Cell Biology
Polynucleotide kinase phosphatase (PNKP) has enzymatic activities as 3′-phosphatase and 5′-kinase of DNA ends to promote DNA ligation and repair. Here, we show that cyclin-dependent kinases (CDKs) regulate the phosphorylation of threonine 118 (T118) in PNKP. This phosphorylation allows recruitment to the gapped DNA structure found in single-strand DNA (ssDNA) nicks and/or gaps between Okazaki fragments (OFs) during DNA replication. T118A (alanine)-substituted PNKP-expressing cells exhibited an accumulation of ssDNA gaps in S phase and accelerated replication fork progression. Furthermore, PNKP is involved in poly (ADP-ribose) polymerase 1 (PARP1)-dependent replication gap filling as part of a backup pathway in the absence of OFs ligation. Altogether, our data suggest that CDK-mediated PNKP phosphorylation at T118 is important for its recruitment to ssDNA gaps to proceed with OFs ligation and its backup repairs via the gap-filling pathway to maintain genome stability.
-
- Cell Biology
Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.
