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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 [ChIP-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 [RNA-seq]

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Functional analysis of CTCF sites associated with cytokine-sensing mammary-specific enhancers in the complex casein locus

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

2017-03-24 | GSE95758 | GEO

Functional analysis of CTCF sites associated with cytokine-sensing mammary-specific enhancers in the complex casein locus [ChIP-seq]

Project description:The zinc finger protein CTCF has been invoked in establishing functional boundaries between genes and thereby controlling enhancer activities. However, there is limited genetic evidence to support such a concept. We have now addressed this question in a locus containing five mammary-specific genes controlled by enhancers. We have identified four CTCF binding sites in the casein locus, two at the outside boundaries and two associated with a super-enhancer. Individual deletions of these sites from the mouse genome did not alter expression of the five casein genes and Odam. However, deletion of the border CTCF site separating the Csn1s1 enhancer from non-mammary genes resulted in the activation of Sult1d1 at a distance of more than 95 kb but not the more proximal Sult1e1 gene. Loss of this CTCF site led to de novo interactions between the Csn1s1 enhancer and the Sult1d1 promoter but not with the silent Sult1e1 gene. Our study suggests that most CTCF sites associated with cell-specific enhancers and super-enhancers have no measurable in vivo activity. Only the loss of one CTCF site led to the induction of a juxtaposed active non-target promoter. Our study also demonstrated that cell-specific enhancers are unable to activate juxtaposed silent non-target promoters.

2017-03-24 | GSE92591 | GEO

Assessing eRNAs associated with a cytokine-sensing mammary super-enhancer

Project description:Enhancers are transcription factor platforms that also bind RNA polymerase II and generate enhancer RNAs (eRNA). Although eRNAs have been suggested as predictors of enhancer activities and possibly key components facilitating transcription, there is little genetic evidence to support this. We address the biology of eRNAs in vivo and investigate eRNA patterns, expression levels and possible functions within a mammary-specific super-enhancer that is composed of three units with distinct transcriptional capacities. We show that eRNA levels do not correspond with the activities of their respective enhancer units. However, changes in eRNA expression upon deletion of individual enhancer units reflect the change in overall super-enhancer activity. These data provide genetic evidence that eRNA levels are not a reliable readout of individual enhancers, but they predict superenhancer activity in the absence of constituent elements.

2018-06-01 | GSE104206 | GEO

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