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An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE129067 | GEO | 2019/10/04

REPOSITORIES: GEO

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An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo.

Project description:Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5?Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.

| S-EPMC6821807 | biostudies-literature

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo (Hi-C)

Project description:High-resolution chromosome conformation capture-sequencing of RE6-9 heterozygous mutants. We investigated the three-dimensional organization of the Scn5a-Scn10a locus in whole hearts of RE6-9 heterozyous mutants and wildtype littermates. Viewpoint were set on enhancer 1 (enh1, located in the intronic region of Scn10a) and the Scn5a promoter (P1_2). The liver of FVB mice was used as controle tissue to determine the specificity of the Scn5a-Scn10a interaction domain in the heart.

2019-10-04 | GSE129062 | GEO

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo (RNA-Seq)

Project description:Whole transcriptome analysis of RE6-9 heterozygous mutants

2019-10-04 | GSE123440 | GEO

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

Project description:An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

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An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo (Hi-C)

Project description:An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo (Hi-C)

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An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo (RNA-Seq)

Project description:An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo (RNA-Seq)

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Chromatin topology and the timing of enhancer function at the HoxD locus

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-10 | GSE154189 | GEO

Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-06-06 | GSE127144 | GEO

Intra-Vk Cluster Recombination Shapes the Ig Kappa Locus Repertoire

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-01-01 | GSE140677 | GEO

Dynamic interplay between enhancer-promoter topology and gene activity.

Project description:A long-standing question in gene regulation is how remote enhancers communicate with their target promoters, and specifically how chromatin topology dynamically relates to gene activation. Here, we combine genome editing and multi-color live imaging to simultaneously visualize physical enhancer-promoter interaction and transcription at the single-cell level in Drosophila embryos. By examining transcriptional activation of a reporter by the endogenous even-skipped enhancers, which are located 150 kb away, we identify three distinct topological conformation states and measure their transition kinetics. We show that sustained proximity of the enhancer to its target is required for activation. Transcription in turn affects the three-dimensional topology as it enhances the temporal stability of the proximal conformation and is associated with further spatial compaction. Furthermore, the facilitated long-range activation results in transcriptional competition at the locus, causing corresponding developmental defects. Our approach offers quantitative insight into the spatial and temporal determinants of long-range gene regulation and their implications for cellular fates.

| S-EPMC6119122 | biostudies-literature

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