The human β‐globin enhancer LCR HS2 plays a role in forming a TAD by activating chromatin structure at neighboring CTCF sites

Kim, Jiwook; Kang, Jin Gu; Kim, Yea Woon; Kim, AeRi

doi:10.1096/fj.202002337r

Cited by 5 publications

(4 citation statements)

References 44 publications

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“…By using a unique, bottom-up approach of building many different regulatory landscapes in an inactive chromatin environment, we provide experimental evidence for an emerging model 20 , 24 , 26 , 27 , 31 , 51 , 52 in which the concerted action of tissue-specific transcription factors at enhancers serves two purposes: (1) they enable recruitment of co-factors, together with which they can stimulate initiation and elongation of the transcriptional machinery at gene promoters, and (2) they enable recruitment of cohesin, which, presumably through DNA extrusion, locally stimulates looping and contacts with and between more distal sequences, to form contact domains. We here show that cohesin recruitment is necessary for enhancers to activate distant, but not proximal, genes.…”

Section: Discussionmentioning

confidence: 99%

Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

Rinzema

Sofiadis

Tjalsma

et al. 2022

Nat Struct Mol Biol

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Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role of stimulating transcription initiation and elongation from target gene promoters and a role of recruiting cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping and the activation of distal target genes.

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Section: Discussionmentioning

confidence: 99%

Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

Rinzema

Sofiadis

Tjalsma

et al. 2022

Nat Struct Mol Biol

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“…Erythroid‐specific transcription factors such as GATA1, TAL1, KLF1, and NF‐E2 are required for the LCR HSs‐target gene interaction 9,24,49–51 . GATA1 appears to recruit histone acetyltransferases such as CBP and p300 into enhancer and then transfer to the promoter of β‐globin gene 23,24,52 . The binding of CTCF insulator factor affect positively the interaction 53,54 .…”

Section: Discussionmentioning

confidence: 99%

“…9,24,49-51 GATA1 appears to recruit histone acetyltransferases such as CBP and p300 into enhancer and then transfer to the promoter of βglobin gene. 23,24,52 The binding of CTCF insulator factor affect positively the interaction. 53,54 However, recent studies using cell imaging have shown that the distance between the enhancer and promoter is not correlated with gene transcription in the Sox2 locus, 12 and enhancers and promoters are further separated by higher transcription activation in the Shh locus, 11 suggesting that enhancer-promoter looping is not necessary for the activation of all genes.…”

Section: Erythroid Genes Enhancermentioning

confidence: 99%

Hematopoietic/erythroid enhancers activate nearby target genes by extending histone H3K27ac and transcribing intergenic RNA

2023

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Enhancers activate gene transcription remotely, which requires tissue specific transcription factors binding to them. GATA1 and TAL1 are hematopoietic/erythroid‐specific factors and often bind together to enhancers, activating target genes. Interestingly, we found that some hematopoietic/erythroid genes are transcribed in a GATA1‐dependent but TAL1‐independnet manner. They appear to have enhancers within a relatively short distance. In this study, we paired highly transcribed hematopoietic/erythroid genes with the nearest GATA1/TAL1‐binding enhancers and analyzed these putative enhancer‐gene pairs depending on distance between them. Enhancers located at various distances from genes in the pairs, which was not related to transcription level of the genes. However, genes with enhancers at short distances away tended to be transcriptionally unaffected by TAL1 depletion. Histone H3K27ac extended from the enhancers to target genes. The H3K27ac extension was maintained without TAL1, even though it disappeared owing to the loss of GATA1. Intergenic RNA was highly transcribed from the enhancers to nearby target genes, independent of TAL1. Taken together, TAL1‐independent transcription of hematopoietic/erythroid genes appears to be promoted by enhancers present in a short distance. These enhancers are likely to activate nearby target genes by tracking the intervening regions.

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“…The ChIP-seq analysis was carried out as described [ 17 ]. ChIP-seq raw reads were qualified by excluding input reads with poor quality values (quality score 20) and then aligned to the human reference (hg19) genome using Bowtie2 [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Histone H3K4me1 strongly activates the DNase I hypersensitive sites in super-enhancers than those in typical enhancers

Kang

Kim

2021

Bioscience Reports

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Super-enhancers, which consist of multiple enhancer elements, are occupied by master transcription factors and coactivators, such as Mediator, and are highly acetylated at histone H3K27. Here, we have characterized the super-enhancers in terms of DNase I hypersensitive sites (DHSs) by analyzing publicly available ChIP-seq and DNase-seq data of K562 cells and compared to the DHSs in typical enhancers. DHSs in the super-enhancers were highly marked by histone H3K4me1 than DHSs in typical enhancers. Loss of H3K4me1 by the deletion of catalytic domains in histone methyltransferases MLL3 and MLL4 remarkably decreased histone H3K27ac and histone H3 depletion at super-enhancer DHSs than at typical enhancer DHSs. The levels of enhancer RNA (eRNA) transcripts and mRNA transcripts from the putative target genes were notably reduced at and near super-enhancer DHSs than typical enhancer DHSs following H3K4me1 loss. These results indicate that histone H3K4me1 is a marker for DHSs in super-enhancers and that this modification has a more significant impact on the activation of super-enhancer DHSs than typical enhancer DHSs.

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The human β‐globin enhancer LCR HS2 plays a role in forming a TAD by activating chromatin structure at neighboring CTCF sites

Cited by 5 publications

References 44 publications

Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

Hematopoietic/erythroid enhancers activate nearby target genes by extending histone H3K27ac and transcribing intergenic RNA

Histone H3K4me1 strongly activates the DNase I hypersensitive sites in super-enhancers than those in typical enhancers

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