Heterodimerization of Tfap2 pioneer factors drives epigenomic remodeling during neural crest specification
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PROVIDER: PRJNA523595 | ENA |
REPOSITORIES: ENA
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Project description:Cell fate commitment is a stepwise process, in which multipotent progenitors transition through sequential regulatory states as they become fate restricted. Recent studies have highlighted the extensive transcriptomic shifts that typify cell differentiation, but our understanding of the epigenetic mechanisms underlying these changes is still superficial. To examine how chromatin states are reorganized during cell fate commitment 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 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:The neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant versus wild-type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its previously well-described role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from ‘permissive’ to ‘repressive’ nucleosome/chromatin organisation to maintain multipotency and define cell fates.
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Project description:Laser capture microdissection (LCM) was used to isolate cells from the principal critical micro-regions, whose development, differentiation and signaling interactions are responsible for the construction of the mammalian face. At E8.5, as migrating neural crest cells begin to exit the neural fold/epidermal ectoderm boundary, we examined the facial mesenchyme, composed of neural crest and paraxial mesoderm cells, as well as cells from adjacent neuroepithelium We performed single cell studies to better define the gene expression states of the early E8.5 pioneer neural crest cells and paraxial mesoderm, and present microarray data detailing expression patterns within these embryonic cell populations. Mouse emrbyos were harvested at developmental stage E8.5 and single cells were captured from the neuroepithilium, neural crest, and paraxial mesoderm. RNA was extracted, labelled, and quantified using the Mouse ST-l microarray.
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Project description:The transcription factors OCT4 and SOX2 play an essential role in the establishment and maintenance of pluripotent embryonic stem cells (ESCs). Yet, their function in specialized stem cell populations is still poorly understood. Here, we show that the OCT4 and SOX2 work as dimers to regulate the epigenomic landscape of neural crest cells. By isolating primary neural crest cells at a range of developmental stages, we characterized the transcriptomic and epigenomic changes that take place during specification, migration, and early differentiation. Analysis of these datasets revealed that the OCT4/SOX2 dimer promotes an epigenomic signature inherent to the multipotent neural crest. We found that the emergence of this epigenomic state requires the translocation of OCT4/SOX2 to tissue-specific cis-regulatory regions. By examining genome organization during the induction of hESCs into neural crest cells, we observed that the patterns of genomic occupancy of the dimer are modified during cell fate commitment. Dimer translocation is guided by neural crest-specific pioneer transcription factors, which physically interact with the OCT4/SOX to modify their genomic targets. Our results demonstrate how the ESC pluripotency program is repurposed in specialized stem cells to control chromatin organization and define the developmental potential of embryonic progenitors.
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Project description:The transcription factors OCT4 and SOX2 play an essential role in the establishment and maintenance of pluripotent embryonic stem cells (ESCs). Yet, their function in specialized stem cell populations is still poorly understood. Here, we show that the OCT4 and SOX2 work as dimers to regulate the epigenomic landscape of neural crest cells. By isolating primary neural crest cells at a range of developmental stages, we characterized the transcriptomic and epigenomic changes that take place during specification, migration, and early differentiation. Analysis of these datasets revealed that the OCT4/SOX2 dimer promotes an epigenomic signature inherent to the multipotent neural crest. We found that the emergence of this epigenomic state requires the translocation of OCT4/SOX2 to tissue-specific cis-regulatory regions. By examining genome organization during the induction of hESCs into neural crest cells, we observed that the patterns of genomic occupancy of the dimer are modified during cell fate commitment. Dimer translocation is guided by neural crest-specific pioneer transcription factors, which physically interact with the OCT4/SOX to modify their genomic targets. Our results demonstrate how the ESC pluripotency program is repurposed in specialized stem cells to control chromatin organization and define the developmental potential of embryonic progenitors.
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Project description:The transcription factors OCT4 and SOX2 play an essential role in the establishment and maintenance of pluripotent embryonic stem cells (ESCs). Yet, their function in specialized stem cell populations is still poorly understood. Here, we show that the OCT4 and SOX2 work as dimers to regulate the epigenomic landscape of neural crest cells. By isolating primary neural crest cells at a range of developmental stages, we characterized the transcriptomic and epigenomic changes that take place during specification, migration, and early differentiation. Analysis of these datasets revealed that the OCT4/SOX2 dimer promotes an epigenomic signature inherent to the multipotent neural crest. We found that the emergence of this epigenomic state requires the translocation of OCT4/SOX2 to tissue-specific cis-regulatory regions. By examining genome organization during the induction of hESCs into neural crest cells, we observed that the patterns of genomic occupancy of the dimer are modified during cell fate commitment. Dimer translocation is guided by neural crest-specific pioneer transcription factors, which physically interact with the OCT4/SOX to modify their genomic targets. Our results demonstrate how the ESC pluripotency program is repurposed in specialized stem cells to control chromatin organization and define the developmental potential of embryonic progenitors.
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Project description:The transcription factors OCT4 and SOX2 play an essential role in the establishment and maintenance of pluripotent embryonic stem cells (ESCs). Yet, their function in specialized stem cell populations is still poorly understood. Here, we show that the OCT4 and SOX2 work as dimers to regulate the epigenomic landscape of neural crest cells. By isolating primary neural crest cells at a range of developmental stages, we characterized the transcriptomic and epigenomic changes that take place during specification, migration, and early differentiation. Analysis of these datasets revealed that the OCT4/SOX2 dimer promotes an epigenomic signature inherent to the multipotent neural crest. We found that the emergence of this epigenomic state requires the translocation of OCT4/SOX2 to tissue-specific cis-regulatory regions. By examining genome organization during the induction of hESCs into neural crest cells, we observed that the patterns of genomic occupancy of the dimer are modified during cell fate commitment. Dimer translocation is guided by neural crest-specific pioneer transcription factors, which physically interact with the OCT4/SOX to modify their genomic targets. Our results demonstrate how the ESC pluripotency program is repurposed in specialized stem cells to control chromatin organization and define the developmental potential of embryonic progenitors.
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