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

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

PROVIDER: PRJNA508757 | ENA |

REPOSITORIES: ENA

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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.

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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.

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

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

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

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Project description:The HoxD gene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different sub-groups of Hoxd genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate separately from two TADs flanking HoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory sub-modules. To understand the importance of this particular regulatory topology to control Hoxd gene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation of Hoxd genes illustrates the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts is eventually resumed, showing that the presence of enhancers sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavourable orientation of CTCF sites.

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Chromatin topology and the timing of enhancer function at the HoxD locus [RNA-seq]

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