Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE217617 | GEO | 2022/11/21
REPOSITORIES: GEO
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Project description:Mammalian sex is determined by a network of antagonistic genes that are well characterized. However, its non-coding regulation is still largely unknown. Here we explore the 3D chromatin landscape of sex determination in vivo. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis approach that identifies 3D regulatory hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, which deletion results in male-to-female sex reversal.
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Project description:Extrachromsomal DNA (ecDNA) are prevalent in human cancers and are associated with high oncogene expression as well as altered chromatin. Here we show that multiple ecDNAs cluster in the nucleus during interphase to form ecDNA hubs, where oncogene transcription preferentially occurs. Single-cell multiomics, single-molecule sequencing, and 3D enhancer connectome reveal MYC ecDNAs are heterogenous in primary sequence and that ecDNA hubs support ectopic and intermolecular enhancer-promoter interactions. Bromodomain-containing protein 4 (BRD4) extensively occupies ecDNA regulatory elements, and inhibition by JQ1 disperses ecDNA hubs and preferentially reduces ecDNA oncogene transcription. Two amplified oncogenes can intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs – nuclear bodies of many ecDNAs tethered by proteins – are platforms for cooperative oncogene transcription. The recognition of ecDNA hubs as units of oncogene function and diversification has potentially broad implications for cancer cell evolution and therapy.
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Project description:Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) genome organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching and promotes the formation of long-range chromatin hubs during induced B cell to macrophage transdifferentiation. A large intrinsically disordered region (IDR) enables CEBPA to undergo in vitro phase separation and to co-condense with transcriptional partners, which is at least partially mediated by aromatic residues. Furthermore, CEBPA forms visible nuclear condensates in transdifferentiating B cells that co-localize with co-activator condensates and recover rapidly upon photobleaching. Finally, native CEBPA-expressing cell types such as primary granulocyte-macrophage progenitors (GMPs), liver cells and trophectoderm cells also reveal nuclear CEBPA condensates and long-range 3D chromatin hubs at CEBPA-bound regions. These findings support a model in which CEBPA acts as a 3D genome structural organizer and suggest that this effect is mediated at least in part by its phase-separation capacity.
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Project description:CCCTC-binding factor (CTCF), a ubiquitously expressed architectural protein, has emerged as a key regulator of cell identity gene transcription. However, the precise molecular mechanism underlying specialized functions of CTCF remains elusive. Here, we investigate the mechanism through integrative analyses of primary hepatocytes, myocytes, and B cells from mouse and human. We demonstrate that CTCF cooperates with lineage-specific pioneer transcription factors (TFs), including MyoD, FOXA, and PU.1, to control cell identity at 1D and 3D levels. At the 1D level, pioneer TFs facilitate lineage-specific CTCF occupancy via opening chromatin. At the 3D level, CTCF and pioneer TFs form regulatory hubs to govern the expression of cell identity genes. This mechanism is validated using MyoD-null mice, CTCF knockout mice, and CRISPR editing during myogenic differentiation. Collectively, these findings uncover a general mechanism whereby CTCF acts as a cell identity cofactor to control cell identity genes via orchestrating regulatory hubs with pioneer TFs.
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Project description:The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex-determining factor SRY as the basic-helix-loop-helix (bHLH) transcription factor TCF21. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response element both in vitro and in vivo during male sex determination. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to promote precursor Sertoli cell differentiation. Therefore, SRY acts directly on the Tcf21 promoter to, in part, initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development.
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Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2020-11-25 | GSE159985 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
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