CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85108 | GEO | 2016/12/10
SECONDARY ACCESSION(S): PRJNA336182
REPOSITORIES: GEO
Similar Datasets
Project description:Enhancer regions and transcription start sites of estrogen-target regulated genes are connected by means of Estrogen Receptor long-range chromatin interactions. Yet, the complete molecular mechanisms controlling the transcriptional output of engaged enhancers and subsequent activation of coding genes remain elusive. Here, we report that CTCF binding to enhancer RNAs is enriched when breast cancer cells are stimulated with estrogen. CTCF binding to enhancer regions results in modulation of estrogen-induced gene transcription by preventing Estrogen Receptor chromatin binding and by hindering the formation of additional enhancer-promoter ER looping. Furthermore, the depletion of CTCF facilitates the expression of target genes associated with cell division and increases the rate of breast cancer cell proliferation. We have also uncovered a genomic network connecting loci enriched in cell cycle regulator genes to nuclear lamina that mediates the CTCF function. The nuclear lamina and chromatin interactions are regulated by estrogen-ER. We have observed that the chromatin loops formed when cells are treated with estrogen establish contacts with the nuclear lamina. Once there, the portion of CTCF associated with the nuclear lamina interacts with enhancer regions, limiting the formation of ER loops and the induction of genes present in the loop. Collectively, our results reveal an important, unanticipated interplay between CTCF and nuclear lamina to control the transcription of ER target genes, which has great implications in the rate of growth of breast cancer cells.
| S-EPMC5159541 | biostudies-literature
Project description:In our work we used high-throughput sequencing methods to get insight in the role of CTCF in ER-mediated gene regulation in luminal breast cancer cells. After assessing genome-wide binding of CTCF, ER, FOXA1 and Lamin B in MCF7 cells treated with estrogen for different time points, we could correlate the interaction to the chromatin with estrogen-induced de novo transcription (from GRO-seq data) and loop formation (from ChIA-PET, Fullwood et al., 2009). We observed that CTCF binding correlates with ER-mediated transcription and its depletion can affect ER-ER loop formation and subsequently gene expression.
2016-12-10 | GSE85106 | GEO
Project description:In our work we used high-throughput sequencing methods to get insight in the role of CTCF in ER-mediated gene regulation in luminal breast cancer cells. After assessing genome-wide binding of CTCF, ER, FOXA1 and Lamin B in MCF7 cells treated with estrogen for different time points, we could correlate the interaction to the chromatin with estrogen-induced de novo transcription (from GRO-seq data) and loop formation (from ChIA-PET, Fullwood et al., 2009). We observed that CTCF binding correlates with ER-mediated transcription and its depletion can affect ER-ER loop formation and subsequently gene expression.
2016-12-10 | GSE85088 | GEO
Project description:CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions
| PRJNA336182 | ENA
Project description:HMGN1, an abundant nucleosomal binding protein, can affect both the chromatin higher order structure and the modification of nucleosomal histones, but it alters the expression of only a subset of genes. We investigated specific gene targeting by HMGN1 in the context of estrogen induction of gene expression. Knockdown and overexpression experiments indicated that HMGN1 limits the induction of several estrogen-regulated genes, including TFF1 and FOS, which are induced by estrogen through entirely distinct mechanisms. HMGN1 specifically interacts with estrogen receptor alpha (ER alpha), both in vitro and in vivo. At the TFF1 promoter, estrogen increases HMGN1 association through recruitment by the ER alpha. HMGN1 S20E/S24E, although deficient in binding nucleosomal DNA, still interacts with ER alpha and, strikingly, still represses estrogen-driven activation of the TFF1 gene. On the FOS promoter, which lacks the ER alpha binding sites, constitutively bound serum response factor (SRF) mediates estrogen stimulation. HMGN1 also interacts specifically with SRF, but HMGN1 S20E/S24E does not. Consistent with the protein interactions, only wild-type HMGN1 significantly inhibits the estrogen-driven activation of the FOS gene. Mechanistically, the inhibition of estrogen induction of several ER alpha-associated genes, including TFF1, by HMGN1 correlates with decreased levels of acetylation of Lys9 on histone H3. Together, these findings indicate that HMGN1 regulates the expression of particular genes via specific protein-protein interactions with transcription factors at target gene regulatory regions.
| S-EPMC2169410 | biostudies-literature
Project description:Estrogen modulates gene expression through interactions with estrogen receptors (ERs) that bind chromosomal target genes. Recent studies have suggested an interaction between the cytoskeletal system and estrogen signaling; these have implicated a role of cytoplasmic microtubules in scaffolding ERalpha and enhancing nongenomic function; in addition, other experiments demonstrate that dynein light chain 1 may chaperone ERalpha to the nucleus, indirectly increasing transcriptional potency. Actin/myosin and dynein light chain 1 are also required for estrogen-mediated chromosomal movement that is required for transcriptional up-regulation of ERalpha targets. We present evidence that the dynactin component, p150/glued, directly influences the potency of nuclear ER function. Increasing the stoichiometric ratio of p150/glued and ERalpha by overexpression enhances estrogen responses. ERalpha enhancement by p150/glued does not appear to be influenced by shifts in subcellular localization because microtubule disruption fails to increase nuclear ERalpha. Rather, we find that modest amounts of p150/glued reside in the nucleus of cells, suggesting that it plays a direct role in nuclear transcription. Notably, p150/glued is recruited to the pS2 promoter in the presence of hormone, and, in MCF-7 cells, knockdown of p150/glued levels reduces estrogen-dependent transcription. Our results suggest that p150/glued modulates estrogen sensitivity in cells through nuclear mechanisms.
| S-EPMC2675952 | biostudies-literature
Project description:A conserved region in the hormone-dependent activation domain AF2 of nuclear receptors plays an important role in transcriptional activation. We have characterized a novel nuclear protein, RIP140, that specifically interacts in vitro with this domain of the estrogen receptor. This interaction was increased by estrogen, but not by anti-estrogens and the in vitro binding capacity of mutant receptors correlates with their ability to stimulate transcription. RIP140 also interacts with estrogen receptor in intact cells and modulates its transcriptional activity in the presence of estrogen, but not the anti-estrogen 4-hydroxytamoxifen. In view of its widespread expression in mammalian cells, RIP140 may interact with other members of the superfamily of nuclear receptors and thereby act as a potential co-activator of hormone-regulated gene transcription.
| S-EPMC394449 | biostudies-other
Project description:The genome is organized via CTCF-cohesin-binding sites, which partition chromosomes into 1-5 megabase (Mb) topologically associated domains (TADs), and further into smaller sub-domains (sub-TADs). Here we examined in vivo an ∼80 kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ∼1 Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF-cohesin sites that 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 adjacent upstream CTCF-cohesin-binding sites. 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 delimit the region of chromatin to which enhancers have access and within which they interact with receptive promoters.
| S-EPMC5540176 | biostudies-literature
Project description:This project identified that TRIM28 can modulate progesterone and estrogen signaling in both human and mouse endometrium to regulate its normal functions during pregnancy. TRIM28 showed proximal localization and co-immunoprecipitation with PR and ERalpha. The ablation of TRIM28 can inhibit the chromatin binding activity of PR and ERalpha leading to disrupted estrogen and progesterone signaling. This immunoprecipitation using TRIM28 antibody was performed in pre-decidual human endometrial stromal cells (HESCs) without any hormone treatment. The potential interacting proteins of TRIM28 was analyzed using mass spec.
2023-07-05 | MSV000092346 | MassIVE
Project description:Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERα.
| S-EPMC4848761 | biostudies-literature