Heterodimerization of Tfap2 pioneer factors drives epigenomic remodeling during neural crest specification
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ABSTRACT:
PROVIDER: PRJNA523595 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10279638_1.fastq.gz | Fastqsanger.gz | |||
| SRR10279638_2.fastq.gz | Fastqsanger.gz | |||
| SRR10279639_1.fastq.gz | Fastqsanger.gz | |||
| SRR10279639_2.fastq.gz | Fastqsanger.gz | |||
| SRR10279640_1.fastq.gz | Fastqsanger.gz |
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Project description:Cell fate commitment involves the progressive restriction of developmental potential. Recent studies have shown that this process requires not only shifts in gene expression but also an extensive remodeling of the epigenomic landscape. To examine how chromatin states are reorganized during cellular specification in an in vivo system, we examined the function of pioneer factor TFAP2A at discrete stages of neural crest development. Our results show that TFAP2A activates distinct sets of genomic regions during induction of the neural plate border and specification of neural crest cells. Genomic occupancy analysis revealed that the repertoire of TFAP2A targets depends upon its dimerization with paralogous proteins TFAP2C and TFAP2B. During gastrula stages, TFAP2A/C heterodimers activate components of the neural plate border induction program. As neurulation begins, TFAP2A trades partners, and TFAP2A/B heterodimers reorganize the epigenomic landscape of progenitor cells to promote neural crest specification. We propose that this molecular switch acts to drive progressive cell commitment, remodeling the epigenomic landscape to define the presumptive neural crest. Our findings show how pioneer factors regulate distinct genomic targets in a stage-specific manner and highlight how paralogy can serve as an evolutionary strategy to diversify the function of the regulators that control embryonic development.
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Project description:Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underly facial shape variation, yet how those in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest, even during the late migratory phase, results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both Tfap2 members dysregulates numerous midface GRN components involved in midface morphogenesis, patterning, and differentiation. Notably, Alx1/3/4 (Alx) transcript levels are reduced, while ChIP-seq analyses suggest TFAP2 directly and positively regulates Alx gene expression. TFAP2 and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish further implies conservation of this regulatory axis across vertebrates. Consistent with this notion in zebrafish, tfap2a mutants present abnormal alx3 expression patterns, Tfap2a binds alx loci, and tfap2a-alx3 genetic interactions are observed. Together, these data demonstrate TFAP2 paralogs regulate vertebrate midfacial development by activating expression of ALX transcription factors.
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