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Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs [ChIP-Seq]

ABSTRACT: Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution.

ORGANISM(S): Mus musculus

PROVIDER: GSE185772 | GEO | 2022/09/29

REPOSITORIES: GEO

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Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs [DamID]

Project description:Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution.

2022-09-29 | GSE185771 | GEO

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs [WGBS]

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Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs [cHiC]

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Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs [ATAC-Seq]

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Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs [RNA-Seq]

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Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes

Project description:Regulatory landscapes drive complex developmental gene expression but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically-associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD-partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1’s intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42’s unresponsiveness. Rather, Zfp42’s promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome-wide, most TADs contain multiple independently-expressed genes.

2022-09-29 | GSE185775 | GEO

Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus

Project description:Higher order chromatin structure establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of individual loci within a topological domain (TAD) are not fully understood. The cystic fibrosis transmembrane conductance regulator (CFTR) gene provides a paradigm for investigating these mechanisms. CFTR occupies a TAD bordered by CTCF/cohesin binding sites within which are cell-type-selective cis-regulatory elements for the locus. We showed previously that intronic and extragenic enhancers, when occupied by specific transcription factors, are recruited to the CFTR promoter by a looping mechanism to drive gene expression. Here we use a combination of CRISPR/Cas9 editing of cis-regulatory elements and siRNA-mediated depletion of architectural proteins to determine the relative contribution of structural elements and enhancers to the higher order structure and expression of the CFTR locus. We found the boundaries of the CFTR TAD are conserved among diverse cell types and are dependent on CTCF and cohesin complex. Removal of an upstream CTCF-binding insulator alters the interaction profile, but has little effect on CFTR expression. Within the TAD, intronic enhancers recruit cell-type selective transcription factors and deletion of a pivotal enhancer element dramatically decreases CFTR expression, but has minor effect on its 3D structure. Examination of open chromatin region in Caco2 (colorectal adenocarcinoma cells), HBE (primary human bronchial epithelial cells), and primary adult human epididymis cells

2016-01-07 | E-GEOD-74709 | biostudies-arrayexpress

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Project description:FKBP5 is a long glucocorticoid-inducible gene implicated in psychiatric disorders. To investigate the complexities of chromatin interaction frequencies at the FKBP5 topologically associated domain (TAD), we deployed fifteen one-to-all chromatin capture viewpoints near gene promoters, enhancers, introns, and CTCF-loop anchors. This revealed a ‘one-TAD-one-gene’ structure encompassing the FKBP5 promoter and its enhancers. The FKBP5 promoter and its two glucocorticoid-stimulated enhancers roam the entire TAD while displaying subtle cell type-specific interactomes. The FKBP5 TAD consists of two nested CTCF loops that are coordinated by one CTCF site beyond the FKBP5 polyadenylation site and another in its 8th intron, 61 kb further. Loop extension correlates with transcription increases through the intronic CTCF site. This is efficiently compensated for, since the short loop is restored even under high transcription regimes. The boundaries of the FKBP5 TAD consist of divergent CTCF sites, harbor multiple smaller genes and are resilient to glucocorticoid stimulation. Interestingly, both FKBP5 TAD boundaries harbor H3K27me3-marked heterochromatin blocks that may reinforce them. We propose that cis-acting genetic and epigenetic polymorphisms underlying FKBP5 expression variation are likely to reside within a 240 kb region that consists of the FKBP5 TAD, its left sub-TAD, and both its boundaries.

2023-10-15 | GSE136034 | GEO

ChIP-sequencing (ChIP-seq) experiments on female ESCs expressing V5-tagged REX1 and control wild-type Embryonic stem cells (ESCs)

Project description:Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome (XCI) in all female somatic cells. Up-regulation of Xist transcription on the future inactive X chromosome (Xi) acts against Tsix antisense transcription, and spreading of Xist RNA in cis triggers epigenetic changes leading to XCI. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is up-regulated in differentiating mouse embryonic stem cells (ESCs) and activates Xist transcription and XCI. Here, we have identified the pluripotency factor REX1 as a key target of RNF12 in the XCI mechanism. RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout mouse ESCs show an increased level of REX1. Using ChIP-seq, REX1 binding sites were detected in Xist and Tsix regulatory regions. Over-expression of REX1 in female ESCs was found to inhibit Xist transcription and XCI, whereas male Rex1+/- ESCs showed ectopic XCI. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate XCI. Rex1 and Xist are present only in placental mammals, which points to co-evolution of these two genes and XCI. 2 (one control one pulldown) samples

2012-06-12 | E-GEOD-36417 | biostudies-arrayexpress

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