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CTCF Functions as an Insulator for Somatic Genes and a Structural Regulator for Pluripotent Genes during Reprogramming [RNA-seq]

ABSTRACT: CCCTC binding factor (CTCF) has been implicated in mediating chromatin insulation and long-distance interactions between enhancer and promoter. In this study, to study the roles of CTCF in somatic cell reprogramming, we performed RNA-seq, Hi-C, ChIP-seq and ATAC-seq at the specific stage of reprogramming. Through bioinformatics analysis, our data indicated that CTCF promotes enhancer-promoter interactions and chromatin accessibility to regulate the expression of key pluripotency genes; meanwhile, it serves as an insulator to suppress the expression of key somatic genes. Smarca5 loss inhibits CTCF-promoted reprogramming by reversing CTCF insulator activity on MEF-specific genes and leading to incorrect nucleosome positioning adjacent to CTCF binding sites. These findings reveal the dual functions of CTCF as both a structural regulator and insulator in conjunction with a key chromatin remodeler to drive cellular reprogramming towards pluripotency.

ORGANISM(S): Mus musculus

PROVIDER: GSE123641 | GEO | 2022/04/05

REPOSITORIES: GEO

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CTCF Functions as an Insulator for Somatic Genes and a Structural Regulator for Pluripotent Genes during Reprogramming [BL-Hi-C]

Project description:CCCTC binding factor (CTCF) has been implicated in mediating chromatin insulation and long-distance interactions between enhancer and promoter. In this study, to study the roles of CTCF in somatic cell reprogramming, we performed RNA-seq, Hi-C, ChIP-seq and ATAC-seq at the specific stage of reprogramming. Through bioinformatics analysis, our data indicated that CTCF promotes enhancer-promoter interactions and chromatin accessibility to regulate the expression of key pluripotency genes; meanwhile, it serves as an insulator to suppress the expression of key somatic genes. Smarca5 loss inhibits CTCF-promoted reprogramming by reversing CTCF insulator activity on MEF-specific genes and leading to incorrect nucleosome positioning adjacent to CTCF binding sites. These findings reveal the dual functions of CTCF as both a structural regulator and insulator in conjunction with a key chromatin remodeler to drive cellular reprogramming towards pluripotency.

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CTCF Functions as an Insulator for Somatic Genes and a Structural Regulator for Pluripotent Genes during Reprogramming [ChIP-seq]

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CTCF Functions as an Insulator for Somatic Genes and a Structural Regulator for Pluripotent Genes during Reprogramming [ATAC-seq]

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Extensive protein group SUMO modification of repressive chromatin factors distinguishes pluripotent from somatic cells (total proteome)

Project description:Post-translational modification by SUMO is a key regulator of cell identity. In mouse embryonic fibroblasts (MEFs), SUMO impedes reprogramming to pluripotency, while in embryonic stem cells (ESCs), it represses the emergence of totipotent-like cells, suggesting that SUMO targets distinct substrates to preserve somatic and pluripotent states. Using MS-based proteomics, we show that the composition of endogenous SUMOylomes differs dramatically between MEFs and ESCs. In MEFs, SUMO2/3 targets proteins associated with canonical SUMO functions, such as splicing, and transcriptional regulators driving somatic enhancer selection. In contrast, in ESCs, SUMO2/3 primarily modifies highly interconnected repressive chromatin complexes, thereby preventing chromatin opening and transitioning to totipotent-like states. We also characterize several SUMO-modified pluripotency factors and show that SUMOylation of Dppa2 and Dppa4 impedes the conversion to 2-cell-embryo-like states. Altogether, we propose that rewiring the repertoire of SUMO target networks is a major driver of cell fate decision during embryonic development.

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Extensive protein group SUMO modification of repressive chromatin factors distinguishes pluripotent from somatic cells

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Cooperative binding of Oct4, Sox2, and Klf4 with stage-specific transcription factors orchestrates reprogramming [RNA-seq]

Project description:Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription-factors (TFs), and chromatin-states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that early in reprogramming OSK extensively bind somatic-enhancers and initiate their decommissioning by recruiting Hdac1. Concurrently, OSK engage other sites, including specific pluripotency-enhancers, and induce the relocation of somatic TFs to these sites and away from somatic-enhancers, extending somatic-enhancer decommissioning genome-wide. Pluripotency-enhancer selection early in reprogramming occurs predominantly at sites with high OSK-motif densities and requires collaborative binding by OSK. Most pluripotency-enhancers are selected later and occupied by OS and stage-specific-TFs like Esrrb. Overexpression of stage-specific-TFs influences reprogramming efficiency by changing OSK-occupancy, somatic-enhancer decommissioning, and pluripotency-enhancer selection. We propose that collaborative interactions among OSK and with stage-specific-TFs direct both somatic-enhancer decommissioning and pluripotency-enhancer selection, which drives the enhancer reorganization underlying reprogramming

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Cooperative binding of Oct4, Sox2, and Klf4 with stage-specific transcription factors orchestrates reprogramming [ChIP-seq]

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Cooperative binding of Oct4, Sox2, and Klf4 with stage-specific transcription factors orchestrates reprogramming [ATAC-seq]

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Project description:Efficient treatment of Acute Myeloid Leukemia (AML) patients remains a challenge despite recent advances. Here using a CRISPRi screen targeting chromatin factors, we identified BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader modules of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.

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Systematic assessment of ISWI subunits reveals that NURF creates local accessibility for proper CTCF function

Project description:Catalytic activity of the ISWI family of remodelers is critical for nucleosomal organization and transcription factor binding, including the insulator protein CTCF. To define which subcomplex mediates these diverse functions we phenotyped a panel of isogenic mouse stem cell lines each lacking one of six ISWI accessory subunits. Individual deletions of either CERF, RSF1, ACF, WICH or NoRC subcomplexes only moderately affect the chromatin landscape, while removal of the NURF-specific subunit BPTF leads to drastic reduction in chromatin accessibility and Snf2h ATPase localization around CTCF sites. While this reduces distances to the adjacent nucleosomes it only modestly impacts CTCF binding itself. In absence of accessibility, the insulator function of CTCF is nevertheless impaired resulting in lower occupancy of cohesin and cohesin-loading factors, and reduced insulation at these sites, highlighting the need of NURF-mediated remodeling for open chromatin and proper CTCF function. Our comprehensive analysis reveals a specific role for NURF in mediating Snf2h localization and chromatin opening at bound CTCF sites showing that local accessibility is critical for cohesin binding and insulator function.

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