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

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

ORGANISM(S): Mus musculus

PROVIDER: GSE127144 | GEO | 2020/06/06

REPOSITORIES: GEO

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Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [4C-seq]

Project description:Enhancer clusters are platforms occupied at high-density by the transcription machinery to activate lineage-specific genes. However, it is not clear yet whether they are merely a collection of conventional enhancers or represent unique and new types of regulatory elements. Specifically, the question remains whether they activate additional enhancer programs in multigene loci. We addressed this issue in the mouse mammary gland, where genes are highly activated during pregnancy. We identify a 300kb multi-gene locus with twenty-one regulatory elements, including a cytokine-dependent primary enhancer cluster (PEC). Using genome editing in combination with ChIP-seq, RNA-seq and 3C-technologies, we show that the PEC initiates the activation of lineage-specific genes through contacting and activating secondary enhancers. This new framework of enhancer clusters indicates a hitherto unrecognized hierarchy of regulation by which a PEC activates genes via regulating secondary enhancers.

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

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

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Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [ChIP-seq]

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Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [RNA-seq]

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Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [4C-seq]

Project description:Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [4C-seq]

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Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [Hi-C]

Project description:Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus [Hi-C]

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Promoter-enhancer looping and shadow enhancers of the mouse ?A-crystallin locus.

Project description:Gene regulation by enhancers is important for precise temporal and spatial gene expression. Enhancers can drive gene expression regardless of their location, orientation or distance from the promoter. Changes in chromatin conformation and chromatin looping occur to bring the promoter and enhancers into close proximity. ?A-crystallin ranks among one of the most abundantly expressed genes and proteins in the mammalian lens. The ?A-crystallin locus is characterized by a 16?kb chromatin domain marked by two distal enhancers, 5' DCR1 and 3' DCR3. Here we used chromatin conformation capture (3C) analysis and transgenic approaches to analyze temporal control of the mouse ?A-crystallin gene. We find that DCR1 is necessary, but not sufficient alone to drive expression at E10.5 in the mouse lens pit. Chromatin looping revealed interaction between the promoter and the region 3' to DCR1, identifying a novel enhancer region in the ?A-crystallin locus. We determined that this novel enhancer region, DCR1S, recapitulates the temporal control by DCR1. Acting as shadow enhancers, DCR1 and DCR1S are able to control expression in the lens vesicle at E11.5. It remains to be elucidated however, which region of the ?A-crystallin locus is responsible for expression in the lens pit at E10.5.

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