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Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [ATAC-seq]

ABSTRACT: Mammalian genomes are subdivided into large (50-2000 kb) regions of chromatin referred to as Topologically Associating Domains (TADs or sub-TADs). Chromatin within an individual TAD contacts itself more frequently than with regions in surrounding TADs thereby directing enhancer-promoter interactions. In many cases, the borders of TADs are defined by convergently orientated boundary elements associated with CCCTC-binding factor (CTCF), which stabilises the cohesin complex on chromatin and prevents its translocation. This delimits chromatin loop extrusion which is thought to underlie the formation of TADs. However, not all CTCF-bound sites act as boundaries and, importantly, not all TADs are flanked by convergent CTCF sites. Here, we examined the CTCF binding sites within a ~70 kb sub-TAD containing the duplicated mouse α-like globin genes and their five enhancers (5’-R1-R2-R3-Rm-R4-α1-α2-3’). The 5’ border of this sub-TAD is defined by a pair of CTCF sites. Surprisingly, we show that deletion of the CTCF binding sites within and downstream of the α-globin locus leaves the sub-TAD largely intact. The predominant 3’ border of the sub-TAD is defined by a steep reduction in contacts: this corresponds to the transcribed α2-globin gene rather than the CTCF sites at the 3’-end of the sub-TAD. Of interest, the almost identical α1- and α2-globin genes interact differently with the enhancers, resulting in preferential expression of the proximal α1-globin gene which behaves as a partial boundary between the enhancers and the distal α2-globin gene. Together, these observations provide direct evidence that actively transcribed genes can behave as boundary elements.

ORGANISM(S): Mus musculus

PROVIDER: GSE153207 | GEO | 2022/06/01

REPOSITORIES: GEO

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Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [RNA-seq]

Project description:Mammalian genomes are subdivided into large (50-2000 kb) regions of chromatin referred to as Topologically Associating Domains (TADs or sub-TADs). Chromatin within an individual TAD contacts itself more frequently than with regions in surrounding TADs thereby directing enhancer-promoter interactions. In many cases, the borders of TADs are defined by convergently orientated boundary elements associated with CCCTC-binding factor (CTCF), which stabilises the cohesin complex on chromatin and prevents its translocation. This delimits chromatin loop extrusion which is thought to underlie the formation of TADs. However, not all CTCF-bound sites act as boundaries and, importantly, not all TADs are flanked by convergent CTCF sites. Here, we examined the CTCF binding sites within a ~70 kb sub-TAD containing the duplicated mouse α-like globin genes and their five enhancers (5’-R1-R2-R3-Rm-R4-α1-α2-3’). The 5’ border of this sub-TAD is defined by a pair of CTCF sites. Surprisingly, we show that deletion of the CTCF binding sites within and downstream of the α-globin locus leaves the sub-TAD largely intact. The predominant 3’ border of the sub-TAD is defined by a steep reduction in contacts: this corresponds to the transcribed α2-globin gene rather than the CTCF sites at the 3’-end of the sub-TAD. Of interest, the almost identical α1- and α2-globin genes interact differently with the enhancers, resulting in preferential expression of the proximal α1-globin gene which behaves as a partial boundary between the enhancers and the distal α2-globin gene. Together, these observations provide direct evidence that actively transcribed genes can behave as boundary elements.

2022-06-01 | GSE153205 | GEO

Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [NG Capture-C]

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Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [ChIP-seq]

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Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (RNA-Seq)

Project description:The genome is organized via CTCF/cohesin binding sites, which partition chromosomes into 1-5Mb topologically associated domains (TADs), and further into smaller contact sub-domains within TADs (sub-TADs; 40-1000kb). Here we examined in vivo an ~80kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ~1Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF/cohesin sites which are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the α-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF/cohesin boundary extends the sub-TAD to the adjacent upstream CTCF/cohesin binding site. The α-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF/cohesin boundaries in this sub-TAD regulate both directionality and specificity of enhancer interactions with surrounding promoters.

2017-06-14 | GSE97870 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (ChIP-Seq)

2017-06-14 | GSE97869 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (Capture-C"

2017-06-14 | GSE97867 | GEO

Tissue-specific CTCF/Cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (ATAC-Seq)

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

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.

2020-11-10 | GSE154188 | GEO

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

2020-11-10 | GSE154187 | GEO

Chromatin topology and the timing of enhancer function at the HoxD locus [4C-seq]

Project description:In tetrapods, the HoxD gene cluster is critical for proper limb formation. 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 emanate from the two TADs flanking HoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several regulatory elements controlling Hoxd genes, initially in a temporal manner and then in the proximal presumptive forearm. T-DOM is divided into two sub-TADs separated by a CTCF-rich boundary defining two regulatory modules with most limb enhancers concentrated in the more distant module. In order to understand the importance of this regulatory topology to elicit a precise Hoxd gene transcription in time and space, we both deleted or inverted this sub-TAD boundary and eliminated the CTCF binding sites. These perturbations caused a time delay in gene activation, which was subsequently resumed. We then inverted the entire T-DOM to change the respective position of the two sub-TADs, which concomitantly introduced a TAD boundary between HoxD and the inverted T-DOM. This re-arrangement had a stronger impact on the early expression and flattened the Hoxd mRNAs levels. The latter effect was rescued by re-granting access to the enhancers upon deletion of the ectopic boundary. These results highlight the importance of regulatory topologies in the temporal control of gene expression. We also show that, along with time, 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.

2020-11-10 | GSE154186 | GEO

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