Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development

Phanstiel, Douglas H.; Bortle, Kevin Van; Spacek, Damek V.; Hess, Gaelen T.; Shamim, Muhammad S.; Machol, Ido; Love, Michael I.; Aiden, E; Bassik, Michael C.; Snyder, M

doi:10.1016/j.molcel.2017.08.006

Cited by 264 publications

(299 citation statements)

References 79 publications

Supporting

Mentioning

255

Contrasting

Order By: Relevance

“…Finally, we asked whether changes similar to those observed at the IL1 locus in RIS cells the IL1 locus cohesin binding pattern was similar to 'normal' IMR90 cells, suggesting that the loop structure at this locus is mostly conserved. However, Phanstiel et al 15 Fig. 9h).…”

mentioning

confidence: 90%

“…Our data indicate that EP contacts in HDFs exhibit plasticity, being susceptible to further modulation towards senescence. EP contacts in lineagecommitted cells also exhibit plasticity towards terminal differentiation 15,21 . Mechanistically, 290 our data suggest that this can be at least in part explained by the formation of transcriptiondependent cohesin islands.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence

Olan

Parry

Schoenfelder

et al. 2019

Preprint

View full text Add to dashboard Cite

Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineagecommitted cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates 35 both local (tissue microenvironment) and systemic (ageing) homeostasis 1,2 . Enhancerpromoter interactions play a key role in gene regulation 3-5 , facilitated by chromatin loops, mostly formed via CCCTC binding factor (CTCF) and cohesin tethering 6-8 . The threedimensional chromatin structure of senescent cells has been characterised 9-11 mostly in terms of macro-domain structures, but its relevance in gene expression remains elusive. 40Here, we use Hi-C and capture 13 to show that oncogenic HRAS-induced senescence (RIS) in human diploid fibroblasts (HDFs) is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks at the 3' end of a subset of active genes, reminiscent of the transcription-driven 'cohesin islands' recently discovered in mouse embryonic fibroblasts 45 deficient in both CTCF and the cohesin release factor Wings apart-like (Wapl) 14 . RIS de novo cohesin peaks are also transcription-dependent and enriched for SASP genes, as exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Cytokine induction is associated with similar cohesin islands appearance and enhancerpromoter rewiring during the terminal differentiation of monocytes to macrophages 15 , but not 50 upon acute TNFa treatment of HDFs 16 . These results suggest that RIS represents a fatedetermined process in which gene expression is regulated beyond the cell type specific 3D chromatin framework, in part through cohesin redistribution. 3 MainOncogene-induced senescence (OIS) has been linked to dynamic alterations of the chromatin 60 landscape, through the formation of three-dimensional heterochromatic foci 17 , altered distributions of histone modifications and chromatin accessibility 2,18 or the appearance of new 'super-enhancers' 19 . While it has been shown that regulation of acute stress-responsive genes can be achieved through transcription factor (TF) recruitment to largely pre-existing enhancer-promoter (EP) contacts 16,20,21 , whether or not a similar mechanism is employed 65 during OIS (sustained oncogenic stress) is unknown. To study gene regulatory mechanisms in the 3D chromatin context at high resolution, we performed in situ Hi-C experiments as well as capture Hi-C (cHi-C) for 62 selected genomic regions of interest ( Supplementary Table 1) in normal growing and oncogenic HRAS-G12V-induced senescent (RIS) IMR90 human diploid fibroblasts (HDFs), using the 4-hydroxytamoxifen (4OHT)-inducible estrogen receptor 70 (ER) HRAS fusion system 22 (ER:HRAS G12V Fig. 1a). Growing (three replicates) and RIS (two replicates) Hi-C libraries yielded a total of 523 and 286 million valid reads respectively, after removal of artefacts and duplicate...

show abstract

mentioning

confidence: 90%

mentioning

confidence: 99%

Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence

Olan

Parry

Schoenfelder

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, our studies reveal that the motif for AP-1 is enriched at new H3K27ac peaks, including those designated as super-enhancers and moreover expression of FOS2L and JUN that encode the AP-1 subunits are upregulated in NSD2 high cells. AP-1 is enriched in activation hubs that connect enhancers and promoters in macrophages 69 , and it may participate in regulating enhancer-promoter contacts in NSD2 overexpressing multiple myeloma cells. Similarly, we speculate that H3K36me2-mediated accessibility promotes binding of CTCF.…”

Section: What Is the Relationship Between Alterations In H3k36me2 H3mentioning

confidence: 99%

NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

Lhoumaud

Badri

Rodriguez-Hernaez

et al. 2019

Preprint

View full text Add to dashboard Cite

CTCF and cohesin play a key role in organizing chromatin into TAD structures. Disruption of a single CTCF binding site is sufficient to change chromosomal interactions leading to alterations in chromatin modifications and gene regulation. However, the extent to which alterations in chromatin modifications can disrupt 3D chromosome organization leading to transcriptional changes is unknown. In multiple myeloma a 4;14 translocation induces overexpression of the histone methyltransferase, NSD2 resulting in expansion of H3K36me2 and shrinkage of antagonistic H3K27me3 domains. Using isogenic cell lines producing high and low levels of NSD2, we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A linear regression model reveals that changes in both CTCF and/or H3K27ac significantly increase the probability that a gene sharing the same insulated domain will be differentially expressed. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.

show abstract

“…The answer is probably yes, since there are small subsets of boundaries that were only detected in two or three cell types, but this appears to be an exception rather than a rule. Similarly, Snyder and co-workers characterized about 16,000 chromatin loops in THP-1 cells, of which only 217 changed significantly upon induction of the monocyte to macrophage differentiation program by phorbol esters (Phanstiel et al, 2017). In line with the cell type-specific TAD hypothesis, ES-cells, have been reported to harbour ES cell-specific loops (Dixon et al, 2015).…”

Section: Discussionmentioning

confidence: 80%

The CTCF Anatomy of Topologically Associating Domains

Nanni

Wang

Manders

et al. 2019

Preprint

View full text Add to dashboard Cite

Topologically associated domains (TADs) are defined as regions of self-interaction. To date, it is unclear how to reconcile TAD structure with CTCF site orientation, which is known to coordinate chromatin loops anchored by Cohesin rings at convergent CTCF site pairs. We first approached this problem by 4C analysis of the FKBP5 locus. This uncovered a CTCF loop encompassing FKBP5 but not its entire TAD. However, adjacent CTCF sites were able to form 'back-up' loops and these were located at TAD boundaries. We then analysed the spatial distribution of CTCF patterns along the genome together with a boundary identity conservation 'gradient' obtained from primary blood cells. This revealed that divergent CTCF sites are enriched at boundaries and that convergent CTCF sites mark the interior of TADs. This conciliation of CTCF site orientation and TAD structure has deep implications for the further study and engineering of TADs and their boundaries.

show abstract

Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development

Cited by 264 publications

References 79 publications

Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence

Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence

NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

The CTCF Anatomy of Topologically Associating Domains

Contact Info

Product

Resources

About