Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation

Siersbæk, Rasmus; Madsen, Jesper Grud Skat; Javierre, Biola-Maria; Nielsen, Ronni; Bagge, Emilie Kristine; Cairns, Jonathan; Wingett, Steven W.; Traynor, Sofie; Spivakov, Mikhail; Fraser, Peter; Mandrup, Susanne

doi:10.1016/j.molcel.2017.04.010

Cited by 202 publications

(216 citation statements)

References 64 publications

(114 reference statements)

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“…On the other hand, there are examples of dynamic promoter-enhancer loops in response to prolonged activation of other signal-responsive factors. Chromosomal contacts measured by Hi-C were enhanced or reduced in concordance with the transcriptional response to progesterone receptor (PR) activation for 6 h in T47D cells (26), and also during early differentiation when measured by promoter capture Hi-C 4h following activation of multiple adipogenesis promoting transcription factors in 3T3-L1 cells (64). In another study, chromosomal contacts, measured by 4C-seq, were enhanced at a subset of EP300 binding loci following activation of GR and/or NF-κB in HeLa cells (8).…”

Section: Discussionmentioning

confidence: 92%

Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

Portuguez

Grbeša

Tal

et al. 2019

Preprint

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The transcription factor glucocorticoid receptor (GR) is a key mediator of stress response and a broad range of physiological processes. How can GR rapidly activate the expression of some genes while repress others, remains an open question due to the challenge to associate GR binding sites (GBSs) to their distant gene targets. Mapping the full 3D scope of GR-responsive promoters using highresolution 4C-seq unravelled spatial separation between chromatin interaction networks of GRactivated and repressed genes. Analysing GR binding sites and other regulatory loci in their functional 3D context revealed that GR sequesters the co-activator Ep300 from active non-GBS enhancers in both activated and repressed gene compartments. While this is sufficient for rapid gene repression, gene activation is countered by productive recruitment of Ep300 to GBS. Importantly, in GR-activated compartments Klf4 binding at non-GBS regulatory elements cluster in 3D with GBS and antagonizes GR activation. In addition, we revealed ROR and Rev-erb transcription factors as novel co-regulators for GR-mediated gene expression.

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Section: Discussionmentioning

confidence: 92%

Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

Portuguez

Grbeša

Tal

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…S1C) that were flanked by CTCF and cohesin (RAD21) and internally occupied by Mediator (MED1) (Fig. S1D), as described previously (14–17). Globally, genomic occupancy of CTCF and cohesin at ZT10 versus ZT22 was very similar at sub-TAD boundaries (Fig.…”

mentioning

confidence: 78%

Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription

Lazar

Marhon

Zhang

et al. 2018

Science

170

177

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Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors (TF) that comprise molecular clocks. Core clock TFs bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. Here we demonstrate that circadian gene expression in mouse liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbα, a core repressive TF of the clock, opposes functional loop formation between Rev-erbα-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 corepressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription.

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“…MED1 is a transcription mediator protein frequently associated with transcriptional enhancers. 63 Two clusters of MED1 ChIP-seq are observed around the Cd274 / Pd-l1 locus after, but not before, differentiation (Clusters 1 and 2; Supplementary Figure 6). Cluster 1 is located in the first intronic region of the Cd274 / Pd-l1 locus, and Cluster 2 in an intergenic region downstream of the gene.…”

Section: Discussionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation

Cited by 202 publications

References 64 publications

Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

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