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3D Chromatin Remodeling Potentiates Transcriptional Programs Driving Cell Invasion [RNA-Seq]

ABSTRACT: Epigenetic mechanisms often play an important role in driving tumor progression towards metastasis. It is less clear that deregulation of chromatin architecture, including topologically associated domains (TADS), contributes to cancer progression. CTCF is a central regulator of three dimensional chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains obscure. We find that the reduced pools of CTCF in hemizygous models potentiates cell invasion. Underlying this phenotype is the activation of oncogenic networks including the PI3K signaling cascade, which presents therapeutic vulnerabilities, especially to mTOR inhibitors. Deregulation of these oncogenic pathways is largely due to the loss of CTCF insulation, allowing a reorganization of long-range chromatin contacts at the subTAD level that is associated with aberrant programming of H3K27 acetylation at enhancer/promoter regions. Thus, lowered CTCF levels lead to chromatin reorganization facilitating pro-invasive transcriptional programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183380 | GEO | 2022/01/01

REPOSITORIES: GEO

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3D Chromatin Remodeling Potentiates Transcriptional Programs Driving Cell Invasion [Hi-C]

Project description:Epigenetic mechanisms often play an important role in driving tumor progression towards metastasis. It is less clear that deregulation of chromatin architecture, including topologically associated domains (TADS), contributes to cancer progression. CTCF is a central regulator of three dimensional chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains obscure. We find that the reduced pools of CTCF in hemizygous models potentiates cell invasion. Underlying this phenotype is the activation of oncogenic networks including the PI3K signaling cascade, which presents therapeutic vulnerabilities, especially to mTOR inhibitors. Deregulation of these oncogenic pathways is largely due to the loss of CTCF insulation, allowing a reorganization of long-range chromatin contacts at the subTAD level that is associated with aberrant programming of H3K27 acetylation at enhancer/promoter regions. Thus, lowered CTCF levels lead to chromatin reorganization facilitating pro-invasive transcriptional programs.

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3D Chromatin Remodeling Potentiates Transcriptional Programs Driving Cell Invasion [ChIP-Seq]

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Architectural protein subclasses shape 3-D organization of genomes during lineage commitment

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Batf pioneers the reorganization of chromatin in developing effector T cells via Ets1-dependent recruitment of Ctcf [ATAC-seq]

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4C-seq analysis of interactions with the Albumin promoter in mouse liver

Project description:Sequencing files provided here include mouse liver ChIP-seq for CTCF and the cohesin subunit Rad21, and 4C-seq analyses in male and female mouse liver centered at an Albumin promoter viewpoint. These files are part of a larger study where we describe features of Topologically Associating Domains (TADs) and their impact on liver gene expression, then use these features to computationally predict subTAD structures not otherwise readily identifiable due to the low resolution of Hi-C. Our findings reveal that CTCF-based subTAD loops maintain key insulating properties of TADs, and support the proposal that subTADs are formed by the same loop extrusion mechanism and contribute to nuclear architecture as intra-TAD scaffolds that further constrain enhancer-promoter interactions. This allows high expression of super enhancer target genes and individual genes within inactive TADs, and may be a broadly conserved mechanism of genomic regulation.

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