Ligand dependent gene regulation by transient ERa clustered enhancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA562143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10020208.fastq.gz | Fastqsanger.gz | |||
| SRR10020209.fastq.gz | Fastqsanger.gz | |||
| SRR10020210.fastq.gz | Fastqsanger.gz | |||
| SRR10020211.fastq.gz | Fastqsanger.gz | |||
| SRR10020212.fastq.gz | Fastqsanger.gz |
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Project description:Unliganded Estrogen receptor alpha (ERa) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ERa binds to several EREs relatively proximal to the pre-marked, or persistent, ERa-bound sites and affects transient but robust gene expression. However, the underlying mechanisms are not fully understood. Here we demonstrate that upon ligand stimulation, persistent sites interact extensively, via chromatin looping, with the proximal transiently ERa-bound sites, forming Ligand Dependent ERa Enhancer Cluster in 3D (LDEC). The E2-target genes are regulated by these clustered enhancers but not by the H3K27Ac super-enhancers. Further, CRISPR-based deletion of TFF1 persistent site disrupts the formation of its LDEC resulting in the loss of E2-dependent expression of TFF1 and its neighboring genes within the same TAD. The LDEC overlap with nuclear ERa condensates that coalesce in a ligand and persistent site dependent manner. Furthermore, formation of clustered enhancers, as well as condensates, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ERa. Our results establish a direct link between ERa condensates, ERa enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion.
2019-11-22 | GSE136302 | GEO
Project description:Unliganded Estrogen receptor alpha (ERα) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ERα binds to several EREs relatively proximal to the pre-marked, unliganded ERα-bound sites and affects transient but robust gene expression. However, the underlying mechanisms are not fully understood. Here we demonstrate that upon ligand stimulation, persistent sites interact extensively, via chromatin looping, with the proximal transiently ERα-bound sites, forming Ligand Dependent ERα Enhancer Cluster in 3D (LDEC). The E2-target genes are regulated by these clustered enhancers but not by the H3K27Ac super-enhancers. Further, CRISPR-based deletion of TFF1 persistent site disrupts the formation of its LDEC resulting in the loss of E2-dependent expression of TFF1 and its neighboring genes within the same TAD. The LDEC overlap with nuclear ERα condensates that coalesce in a ligand and persistent site dependent manner. Furthermore, formation of clustered enhancers, as well as condensates, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ERα. Our results establish, at TFF1 and NRIP1 locus, a direct link between ERα condensates, ERα enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion.
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Project description:Endocrine therapy is the preferred therapeutic strategy for estrogen receptor alpha (ERa)-positive breast cancer, but intrinsic endocrine resistance leads a significant challenge. CCCTC binding factor (CTCF)-mediated hyperactivation of ERa-associated enhancers have been recognized as important molecular mechanism leading to endocrine resistance, yet the underlying molecular mechanism of this process still remains unclear. Here, we found a critical enhancer modulator, Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18), had a global recruitment on gene enhancer combining with CTCF. Consistently, ERa-related enhancer transactivation was highly correlated with increasing BAP18 enrichment. BAP18 interacted with SMARCA1, another nucleosome remodeling factor (NURF) complex subunit, participating modulating CTCF and ERa recruitment on enhancers. Interestingly, BAP18 globally advantaged chromatin accessibility of enhancer regions, especially the sites with CTCF binding, thereby increasing targeted enhancer-promoter looping (E-P looping) by facilitating CTCF recruitment. Our functional studies in multiple culture and aromatase inhibitor (AI)-nonresponse models reveal a critical role of BAP18 in regulating drug tolerance of breast cancer cells and patients. Collectively, our study suggested that BAP18 coordinated with CTCF in transactivating ERa-related enhancers, and exhibited a better understanding about chromatin remodeling and E-P looping mechanism of AI therapy resistance.
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Project description:Endocrine therapy is the preferred therapeutic strategy for estrogen receptor alpha (ERa)-positive breast cancer, but intrinsic endocrine resistance leads a significant challenge. CCCTC binding factor (CTCF)-mediated hyperactivation of ERa-associated enhancers have been recognized as important molecular mechanism leading to endocrine resistance, yet the underlying molecular mechanism of this process still remains unclear. Here, we found a critical enhancer modulator, Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18), had a global recruitment on gene enhancer combining with CTCF. Consistently, ERa-related enhancer transactivation was highly correlated with increasing BAP18 enrichment. BAP18 interacted with SMARCA1, another nucleosome remodeling factor (NURF) complex subunit, participating modulating CTCF and ERa recruitment on enhancers. Interestingly, BAP18 globally advantaged chromatin accessibility of enhancer regions, especially the sites with CTCF binding, thereby increasing targeted enhancer-promoter looping (E-P looping) by facilitating CTCF recruitment. Our functional studies in multiple culture and aromatase inhibitor (AI)-nonresponse models reveal a critical role of BAP18 in regulating drug tolerance of breast cancer cells and patients. Collectively, our study suggested that BAP18 coordinated with CTCF in transactivating ERa-related enhancers, and exhibited a better understanding about chromatin remodeling and E-P looping mechanism of AI therapy resistance.
2022-03-16 | GSE198242 | GEO
Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Experiment Overall Design: Wild type and osteoclast-specific Estrogen Receptor alpha knock-out mice were ovariectomized. The number of both genotypes of mice was eight. The mice of each genotypes were divided to vehicle control and estrogen treated group. Four hours after chemical treatment, the distal 5 mm of the left femurs were harvested after sacrificing by cervical dislocation and total RNAs were purified for Affymetix GeneChip microarray analysis without pooling. Therefore, this experiment consists of four groups with four replicates per group.
2008-06-15 | E-GEOD-7798 | biostudies-arrayexpress
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Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Keywords: Study about estrogen response of osteoclast-specific estrogen receptor alpha mice
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