Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation

Abstract

Summary Enhancers instruct spatio-temporally specific gene expression in a manner tightly linked to higher-order chromatin architecture. Critical chromatin architectural regulators condensin I and condensin II play non-redundant roles controlling mitotic chromosomes. But aspects of interphase condensin loading and function, or in transcription regulation remain unclear. Here we report that both condensin complexes exhibit an unexpected, dramatic estrogen-induced recruitment to estrogen receptor α (ER-α)-bound eRNA+ active enhancers in interphase breast cancer cells, exhibiting non-canonical interaction with ER-α via its DNA-binding domain (DBD). Condensins positively regulate ligand-dependent enhancer activation, at least in part, by recruiting an E3 ubiquitin ligase, HECTD1, to modulate the binding of enhancer-associated coactivators/corepressors, including p300 and RIP140, permitting full eRNA transcription, formation of enhancer:promoter looping and the resultant coding gene activation. Collectively, our results reveal an important, unanticipated transcriptional role of interphase condensins in modulating estrogen-regulated enhancer activation and coding gene transcriptional program.

Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program

“…The identification of ChIP-seq peaks (bound & enriched regions) was performed by using HOMER as previously described ((Li et al, 2015; Liu et al, 2013; Ma and Telese, 2015; Telese et al, 2015). For all the ChIP-seq reads we kept only one tag for each unique genomic position to minimize artifacts due to clonal amplification.…”

“…Following ligand-induced nuclear entry, ERα binds to ~30,000 estrogen response elements (EREs), a subset of which harbor the histone/epigenetic marks associated to enhancers (Carroll et al, 2006; Li et al, 2013; Hah et al, 2013). At putative functional enhancers, ERα promotes the recruitment of co-factors on these enhancers to activate the transcription of enhancer RNA (eRNA) and target coding genes (Li et al, 2015; Liu et al, 2014; Nagarajan et al, 2014). In addition to the coactivator complexes, it appears that additional factors can be critically required.…”

Condensin-mediated chromosome organization in fission yeast

“…As in fission yeast cells, condensin is enriched at highly transcribed genes in higher eukaryotes (Kim et al 2013; Sutani et al 2015). It has recently been shown that condensin mediates gene looping and activation in human cells, and that condensin mutations are significantly accumulated in various cancer types (Li et al 2015; Leiserson et al 2015). Further work in the fission yeast model, addressing how the condensin-TBP interaction contributes to higher-order genome organization, gene regulation, and chromosome segregation, will help elucidate the evolutionarily conserved mechanisms of how condensin organizes eukaryotic genomes and serves as a functional ligature among important cellular processes.…”

CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions

“…Moreover, these regulatory regions are located hundreds of kilobases away from transcription start sites (TSS) of the target gene (2). Cohesin and condensin have recently been shown to positively regulate transcription by modulating enhancer function and enhancer–promoter looping (3,4). Yet, the role of other architectural proteins involved in nuclear organization, such as the transcriptional regulator CCCTC-binding factor (CTCF), is unexplored.…”