Dual role of ZIC2 during neural induction: from pioneer transcription factor to enhancer activator [ChIP-Seq]
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PROVIDER: PRJNA1311599 | ENA |
REPOSITORIES: ENA
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Project description:ZIC2, a member of the Zinc Finger of the Cerebellum family of transcription factors (TFs), plays crucial roles during neural development. In humans, defects in ZIC2 cause holoprosencephaly, a congenital brain malformation characterized by the defective cleavage of cerebral hemispheres due to problems in midline patterning. However, the gene regulatory network (GRN) controlled by ZIC2 and the regulatory mechanisms it employs during neural development remain largely unexplored. Here, we combined a mouse embryonic stem cell (mESC) in vitro differentiation model towards anterior neural progenitors (AntNPCs) with genome editing approaches, bulk and single cell (i.e. Multiome scATAC + scRNAseq) genomic methods to elucidate the precise GRN controlled by ZIC2 and the underlying mechanisms. We found that ZIC2 shows widespread binding throughout the genome already in mESC as well as upon pluripotency exit and neural induction. Despite its extensive binding in mESC, ZIC2 function is dispensable in pluripotent cells due to compensation by ZIC3. In contrast, ZIC2 plays a major regulatory function during neural induction, directly controlling the expression of master regulators implicated in the patterning and morphogenesis of specific brain regions, such as the midbrain (e.g., En1, Lmx1b, Pax2, Wnt1) and the roof plate (e.g., Lmx1a, Wnt3a). Mechanistically, ZIC2 plays a dual role in neural differentiation: (i) during pluripotency exit, ZIC2 acts as a pioneer TF, binding de novo to distal enhancers and promoting their chromatin accessibility; (ii) during neural induction, ZIC2 is essential for the activation of a subset of the previously primed enhancers, which in turn control the expression of major neural patterning regulators and signaling pathways (i.e. WNT) that prevent the premature differentiation of neural progenitors. Overall, our work shows that, by sequentially acting as a promiscuous pioneer and selective activator of enhancer elements, ZIC2 canalizes pluripotent cells towards neural progenitors with rostro-dorsal identities.
2025-08-26 | GSE306567 | GEO
Project description:ZIC2, a member of the Zinc Finger of the Cerebellum family of transcription factors (TFs), plays crucial roles during neural development. In humans, defects in ZIC2 cause holoprosencephaly, a congenital brain malformation characterized by the defective cleavage of cerebral hemispheres due to problems in midline patterning. However, the gene regulatory network (GRN) controlled by ZIC2 and the regulatory mechanisms it employs during neural development remain largely unexplored. Here, we combined a mouse embryonic stem cell (mESC, D0) in vitro differentiation model towards anterior neural progenitors (AntNPCs, D6) with genome editing approaches, bulk and single cell (i.e. Multiome scATAC + scRNAseq) genomic methods to elucidate the precise GRN controlled by ZIC2 and the underlying mechanisms. We found that ZIC2 shows widespread binding throughout the genome already in mESC as well as upon pluripotency exit and neural induction. Despite its extensive binding in mESC, ZIC2 function is dispensable in pluripotent cells due to compensation by ZIC3. In contrast, ZIC2 plays a major regulatory function during neural induction, directly controlling the expression of master regulators implicated in the patterning and morphogenesis of specific brain regions, such as the midbrain (e.g., En1, Lmx1b, Pax2, Wnt1) and the roof plate (e.g., Lmx1a, Wnt3a). Mechanistically, ZIC2 plays a dual role in neural differentiation: (i) during pluripotency exit, ZIC2 acts as a pioneer TF, binding de novo to distal enhancers and promoting their chromatin accessibility; (ii) during neural induction, ZIC2 is essential for the activation of a subset of the previously primed enhancers, which in turn control the expression of major neural patterning regulators and signaling pathways (i.e. WNT) that prevent the premature differentiation of neural progenitors. Overall, our work shows that, by sequentially acting as a promiscuous pioneer and selective activator of enhancer elements, ZIC2 canalizes pluripotent cells towards neural progenitors with rostro-dorsal identities.
2025-08-26 | GSE306563 | GEO
Project description:ZIC2, a member of the Zinc Finger of the Cerebellum family of transcription factors (TFs), plays crucial roles during neural development. In humans, defects in ZIC2 cause holoprosencephaly, a congenital brain malformation characterized by the defective cleavage of cerebral hemispheres due to problems in midline patterning. However, the gene regulatory network (GRN) controlled by ZIC2 and the regulatory mechanisms it employs during neural development remain largely unexplored. Here, we combined a mouse embryonic stem cell (mESC) in vitro differentiation model towards anterior neural progenitors (AntNPCs) with genome editing approaches, bulk and single cell (i.e. Multiome scATAC + scRNAseq) genomic methods to elucidate the precise GRN controlled by ZIC2 and the underlying mechanisms. We found that ZIC2 shows widespread binding throughout the genome already in mESC as well as upon pluripotency exit and neural induction. Despite its extensive binding in mESC, ZIC2 function is dispensable in pluripotent cells due to compensation by ZIC3. In contrast, ZIC2 plays a major regulatory function during neural induction, directly controlling the expression of master regulators implicated in the patterning and morphogenesis of specific brain regions, such as the midbrain (e.g., En1, Lmx1b, Pax2, Wnt1) and the roof plate (e.g., Lmx1a, Wnt3a). Mechanistically, ZIC2 plays a dual role in neural differentiation: (i) during pluripotency exit, ZIC2 acts as a pioneer TF, binding de novo to distal enhancers and promoting their chromatin accessibility; (ii) during neural induction, ZIC2 is essential for the activation of a subset of the previously primed enhancers, which in turn control the expression of major neural patterning regulators and signaling pathways (i.e. WNT) that prevent the premature differentiation of neural progenitors. Overall, our work shows that, by sequentially acting as a promiscuous pioneer and selective activator of enhancer elements, ZIC2 canalizes pluripotent cells towards neural progenitors with rostro-dorsal identities.
2025-08-26 | GSE306566 | GEO
Project description:ZIC2, a member of the Zinc Finger of the Cerebellum family of transcription factors (TFs), plays crucial roles during neural development. In humans, defects in ZIC2 cause holoprosencephaly, a congenital brain malformation characterized by the defective cleavage of cerebral hemispheres due to problems in midline patterning. However, the gene regulatory network (GRN) controlled by ZIC2 and the regulatory mechanisms it employs during neural development remain largely unexplored. Here, we combined a mouse embryonic stem cell (mESC) in vitro differentiation model towards anterior neural progenitors (AntNPCs) with genome editing approaches, bulk and single cell (i.e. Multiome scATAC + scRNAseq) genomic methods to elucidate the precise GRN controlled by ZIC2 and the underlying mechanisms. We found that ZIC2 shows widespread binding throughout the genome already in mESC as well as upon pluripotency exit and neural induction. Despite its extensive binding in mESC, ZIC2 function is dispensable in pluripotent cells due to compensation by ZIC3. In contrast, ZIC2 plays a major regulatory function during neural induction, directly controlling the expression of master regulators implicated in the patterning and morphogenesis of specific brain regions, such as the midbrain (e.g., En1, Lmx1b, Pax2, Wnt1) and the roof plate (e.g., Lmx1a, Wnt3a). Mechanistically, ZIC2 plays a dual role in neural differentiation: (i) during pluripotency exit, ZIC2 acts as a pioneer TF, binding de novo to distal enhancers and promoting their chromatin accessibility; (ii) during neural induction, ZIC2 is essential for the activation of a subset of the previously primed enhancers, which in turn control the expression of major neural patterning regulators and signaling pathways (i.e. WNT) that prevent the premature differentiation of neural progenitors. Overall, our work shows that, by sequentially acting as a promiscuous pioneer and selective activator of enhancer elements, ZIC2 canalizes pluripotent cells towards neural progenitors with rostro-dorsal identities.
2025-08-28 | GSE306666 | GEO
Project description:Dual role of ZIC2 during neural induction: from pioneer transcription factor to enhancer activator [Multiome]
| PRJNA1311125 | ENA
Project description:Dual role of ZIC2 during neural induction: from pioneer transcription factor to enhancer activator [ATAC-Seq]
| PRJNA1311116 | ENA
Project description:Dual role of ZIC2 during neural induction: from pioneer transcription factor to enhancer activator [RNA-Seq]
| PRJNA1311124 | ENA
Project description:RNA-seq transcriptome analysis identified an early requirement for zic2 in periocular neural crest as an activator of alx1, a transcription factor with essential roles in craniofacial and ocular morphogenesis in human and zebrafish
2017-07-14 | GSE99382 | GEO
Project description:FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: First, FOXA facilitate signal-dependent lineage initiation via enhancer priming, and second, FOXA enforce organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.
2021-10-18 | GSE148368 | GEO
Project description:Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors
| PRJNA624086 | ENA