Architectural proteins: regulators of 3D genome organization in cell fate

Gómez-Díaz, Elena; Corcés, Victor G.

doi:10.1016/j.tcb.2014.08.003

Cited by 97 publications

(73 citation statements)

References 82 publications

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“…Our observations are also consistent with the possibility of E␤ scanning the chromatin by making several less-frequent/unstable random contacts with other elements within its target domain and restriction of the target domain by the intervening insulator. This is consistent with the emerging views that dynamic interactions of a variable frequency occur within chromatin domains; interactions between enhancers and their cognate promoters are most frequent and/or stable but may be modulated by CTCF-binding sites residing within the same topologically associated domains (TADs) (40).…”

Section: Pdβ1-djcβ1supporting

confidence: 89%

Influence of a CTCF-Dependent Insulator on Multiple Aspects of Enhancer-Mediated Chromatin Organization

Varma

Rawat

Jalan

et al. 2015

Molecular and Cellular Biology

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Developmental stage-specific enhancer-promoter-insulator interactions regulate the chromatin configuration necessary for transcription at various loci and additionally for VDJ recombination at antigen receptor loci that encode immunoglobulins and T-cell receptors. To investigate these regulatory interactions, we analyzed the epigenetic landscape of the murine T-cell receptor ␤ (TCR␤) locus in the presence and absence of an ectopic CTCF-dependent enhancer-blocking insulator, H19-ICR, in genetically manipulated mice. Our analysis demonstrated the ability of the H19-ICR insulator to restrict several aspects of enhancerbased chromatin alterations that are observed during activation of the TCR␤ locus for transcription and recombination. The H19-ICR insulator abrogated enhancer-promoter contact-dependent chromatin alterations and additionally prevented E␤-mediated histone modifications that have been suggested to be independent of enhancer-promoter interaction. Observed enhancerpromoter-insulator interactions, in conjunction with the chromatin structure of the E␤-regulated domain at the nucleosomal level, provide useful insights regarding the activity of the regulatory elements in addition to supporting the accessibility hypothesis of VDJ recombination. Analysis of H19-ICR in the heterologous context of the developmentally regulated TCR␤ locus suggests that different mechanisms proposed for CTCF-dependent insulator action might be manifested simultaneously or selectively depending on the genomic context and the nature of enhancer activity being curtailed.T ranscriptional insulators regulate the enhancer-promoter communication that orchestrates the epigenetic landscape of specific loci to activate or repress genes in metazoan genomes. Enhancers can regulate their cognate promoters by diverse mechanisms (1, 2). These may involve direct contact with the promoter by looping and/or alteration of the epigenetic landscape of large domains that render them "open," i.e., associated with chromatin modifications that make them accessible to trans-acting factors. Alteration of the large domains could be due to "tracking" of some proteins initially bound at the enhancer or, as proposed during "facilitated tracking," the movement of enhancer itself along the chromatin. Insulators in the vertebrate genomes have been proposed to modulate these interactions by binding to CTCF, a multiZn-finger protein (3). Genome-wide analysis of CTCF demonstrates its crucial role in higher-order chromatin organization that can facilitate enhancer-promoter interactions as well as curtail them depending on the relative positions of these regulatory elements (4). Importantly, insulators block enhancer-promoter communication only when present between them. Several models have been proposed for enhancer blocking, keeping in view the varied mechanisms underlying enhancer activity (5). It has been postulated that the CTCF-bound insulator partitions the enhancer and promoter to topologically distinct chromatin loops and thus prevents their interaction. The i...

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Section: Pdβ1-djcβ1supporting

confidence: 89%

Influence of a CTCF-Dependent Insulator on Multiple Aspects of Enhancer-Mediated Chromatin Organization

Varma

Rawat

Jalan

et al. 2015

Molecular and Cellular Biology

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“…This particular region of HoxD, located between genes strongly and constitutively interacting with either the centromeric (Hoxd13) or the telomeric (Hoxd1, Hoxd4) TADs, may thus display more flexibility, perhaps reflected by the capacity of Hoxd8 or Hoxd12 to switch their contacts from one TAD to the other in various limb cell-types (16). Interestingly, this region is strongly enriched in binding sites for architectural proteins such as CCCTC-binding factor (CTCF) and cohesin (41,42), which are known for their capacity to organize genomic boundaries and domains, in particular at TAD boundaries (43). Whether the presence of several sites bound by CTCF in the sequence targeted by the Hoxd8 to Hoxd12 fosmid play a role in the elongation observed by STORM remains to be tested, however, as CTCF-driven interactions would be expected to increase compaction, rather than the opposite.…”

Section: Discussionmentioning

confidence: 99%

Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states

Fabre

Benke

Joye

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Chromatin condensation plays an important role in the regulation of gene expression. Recently, it was shown that the transcriptional activation of Hoxd genes during vertebrate digit development involves modifications in 3D interactions within and around the HoxD gene cluster. This reorganization follows a global transition from one set of regulatory contacts to another, between two topologically associating domains (TADs) located on either side of the HoxD locus. Here, we use 3D DNA FISH to assess the spatial organization of chromatin at and around the HoxD gene cluster and report that although the two TADs are tightly associated, they appear as spatially distinct units. We measured the relative position of genes within the cluster and found that they segregate over long distances, suggesting that a physical elongation of the HoxD cluster can occur. We analyzed this possibility by super-resolution imaging (STORM) and found that tissues with distinct transcriptional activity exhibit differing degrees of elongation. We also observed that the morphological change of the HoxD cluster in developing digits is associated with its position at the boundary between the two TADs. Such variations in the fine-scale architecture of the gene cluster suggest causal links among its spatial configuration, transcriptional activation, and the flanking chromatin context. DNA FISH | super-resolution microscopy | limb development | topologically associating domains | HoxD

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“…Besides the large blocks of DNA hypomethylation (Hansen et al 2011;Berman et al 2012;Hon et al 2012;Timp et al 2014) and hypermethylation Coolen et al 2010;Forn et al 2013), other alterations as the activation of gene clusters (Bert et al 2013) and the increased somatic mutation rates observed in heterochromatic and late replicating regions (Schuster-Böckler and Lehner 2012;Polak et al 2015) point out that factors regulating high-order chromatin architecture (Dekker et al 2013;Gómez-Díaz and Corces 2014;Feinberg et al 2016) might play a principal role in the remodeling of the cancer genome (Rodriguez et al 2008a;Lizardi et al 2011;Kemp et al 2014;Lay et al 2015;Taberlay et al 2016). The contribution of Alu repeats to the setting and maintenance of chromatin domains and their regulation in normal and cancer cells is still unknown.…”

Section: Alu-related Determinants Of Global Genomic Hypomethylation Amentioning

confidence: 99%

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

et al. 2016

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Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.

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Architectural proteins: regulators of 3D genome organization in cell fate

Cited by 97 publications

References 82 publications

Influence of a CTCF-Dependent Insulator on Multiple Aspects of Enhancer-Mediated Chromatin Organization

Influence of a CTCF-Dependent Insulator on Multiple Aspects of Enhancer-Mediated Chromatin Organization

Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

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