Mechanisms of RING1B and PRC1 complexes in transcriptional activation
RING1B和PRC1复合物在转录激活中的机制
基本信息
- 批准号:10542418
- 负责人:
- 金额:$ 32.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcuteAddressArchitectureBT 474BindingBiological AssayBiological ProcessBreast Cancer CellBreast Cancer ModelBreast Cancer cell lineCellsChIP-seqChemicalsChromatinChromatin StructureClustered Regularly Interspaced Short Palindromic RepeatsComplexCoupledDNADataDevelopmentDistalEndocrineEnhancersEpigenetic ProcessEstrogen Receptor alphaEstrogen receptor positiveEstrogensFeedbackFulvestrantGREB1 geneGene ActivationGene ChipsGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGrowthHi-CHormonalHormonesHybridsLicensingMCF7 cellMalignant NeoplasmsMediatingMetabolismMetastatic breast cancerMultiprotein ComplexesMutationNCOA2 geneNCOA3 geneNeoplasm MetastasisOncogenesOncogenicPRC1 ProteinPhenotypePolycombProcessProliferatingProteinsProteomicsRNARegulator GenesRegulatory ElementReproductionResearchResistanceResolutionRoleSteroid ReceptorsT47DTamoxifenTestingTranscriptional ActivationWorkXenograft Modelcancer cellcofactorcohesinexperimental studygene repressiongenome-widegenome-wide analysishormone therapyhuman diseasein vivomalignant breast neoplasmmutantnoveloverexpressionparalogous genepatient derived xenograft modelpromoterprotein complexrecruitresponsestem cell fatestem cellssteroid hormonetranscriptome sequencingtumortumorigenesis
项目摘要
Project summary
Polycomb group (PcG) complexes are multi-protein, evolutionarily conserved epigenetic machineries that
regulate stem cell fate decisions and early development. Mutation and abnormal expression of Polycomb
Repressive Complex 1 (PRC1) subunits are also implicated in human disease. PRC1 is a protein complex that
was classically thought to mediate transcriptional repression of genes. We and others recently showed that
specific PRC1 complexes, defined by the presence of one of the six mammalian PCGF paralogs, can also
facilitate gene transcription in stem and cancer cells to regulate cell fate decisions and oncogenes. How PRC1
is recruited to chromatin and mediates transcriptional activation is poorly understood. We recently demonstrated
that PRC1 and the estrogen receptor alpha (ER) co-occupy transcriptionally active genes and enhancers to
regulate proliferation of breast cancer cells. ER is functionally activated by the steroid hormone estrogen. Once
activated, ER binds to chromatin and recruits co-activators to regulate fundamental biological processes such
as development, reproduction, metabolism, and cancer. Our new preliminary data show that estrogen induces
rapid and dynamic recruitment to chromatin of RING1B, the core subunit of all PRC1 complexes, to activate
gene transcription in a PRC1-indepenent fashion. Moreover, we found that R-loop formation and ER might be
important for RING1B recruitment to chromatin, suggesting that RING1B is tethered to chromatin by different
mechanisms. Importantly, RING1B is also required for ER recruitment, gene and enhancer transcriptional
activation as well as chromatin organization. Our preliminary 3D chromatin architecture data also revealed that
RING1B/ER-containing enhancers physically interact with estrogen-responsive genes. These results uncover
potential new mechanisms for transcriptional activation mediated by RING1B upon estrogen administration.
Finally, we found that RING1B is overexpressed in metastatic endocrine resistant breast cancer and that
endocrine resistant cells are addicted to RING1B. We hypothesize that RING1B is a novel epigenetic regulator
of estrogen-mediated gene regulation and chromatin architecture, and that RING1B depletion and chemical
inhibition will decrease metastatic endocrine-resistant breast cancer. Here, we propose: to determine how
RING1B is recruited to estrogen-responsive genes (Aim 1), the role of RING1B in enhancer-promoter
interactions during estrogen administration (Aim 2), and the role of RING1B in endocrine resistance (Aim 3). Hi-
C experiments, coupled to genome-wide studies (including gene expression profiles, chromatin accessibility
assays), proteomics, and xenografts and PDX models will be used to address these central questions.
Fundamentally, these findings will expand our understanding of the estrogen response and Polycomb implicated
in broad biological processes including development, cellular metabolism and cancer.
项目摘要
多梳组(PcG)复合物是多蛋白质的、进化上保守的表观遗传机制,
调节干细胞命运决定和早期发育。Polycomb基因突变及异常表达
抑制性复合物1(PRC 1)亚基也与人类疾病有关。PRC 1是一种蛋白质复合物,
传统上被认为是介导基因的转录抑制。我们和其他人最近表明,
由六种哺乳动物PCGF旁系同源物之一的存在所定义的特异性PRC 1复合物也可以
促进干细胞和癌细胞中的基因转录以调节细胞命运决定和致癌基因。如何PRC 1
被募集到染色质并介导转录激活的机制知之甚少。我们最近展示了
PRC 1和雌激素受体α(ER β)共同占据转录活性基因和增强子,
调节乳腺癌细胞的增殖。ER β在功能上被类固醇激素雌激素激活。一旦
一旦被激活,ER β与染色质结合,并招募共激活因子来调节基本的生物学过程,
如发育、生殖、新陈代谢和癌症。我们新的初步数据显示雌激素诱导
RING 1B(所有PRC 1复合物的核心亚基)快速和动态地募集到染色质中,
以PRC 1独立的方式进行基因转录。此外,我们发现,R-环的形成和ER β可能是
重要的RING 1B招募染色质,这表明RING 1B是拴在染色质的不同,
机制等重要的是,RING 1B也是ER β募集、基因和增强子转录
激活以及染色质组织。我们初步的3D染色质结构数据还显示,
含有RING 1B/ER β的增强子与雌激素应答基因物理相互作用。这些结果揭示了
雌激素给药后RING 1B介导的转录激活的潜在新机制。
最后,我们发现RING 1B在转移性内分泌耐药乳腺癌中过表达,
内分泌抵抗细胞对RING 1B上瘾。我们假设RING 1B是一种新的表观遗传调节因子,
雌激素介导的基因调控和染色质结构,以及RING 1B缺失和化学
抑制将减少转移性内分泌抗性乳腺癌。在这里,我们建议:确定如何
RING 1B被募集到雌激素应答基因(Aim 1),RING 1B在增强子-启动子中的作用
雌激素给药期间的相互作用(目的2),以及RING 1B在内分泌抵抗中的作用(目的3)。你好-
C实验,再加上全基因组研究(包括基因表达谱,染色质可及性
分析),蛋白质组学,异种移植和PDX模型将用于解决这些中心问题。
从根本上说,这些发现将扩大我们对雌激素反应和Polycomb牵连的理解。
在包括发育、细胞代谢和癌症在内的广泛的生物过程中。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Lluis Morey', 18)}}的其他基金
Altering the chromostasis and genome stability by modulating histone methylation
通过调节组蛋白甲基化改变染色质和基因组稳定性
- 批准号:
10467535 - 财政年份:2022
- 资助金额:
$ 32.24万 - 项目类别:
Mechanisms of RING1B and PRC1 complexes in transcriptional activation
RING1B和PRC1复合物在转录激活中的机制
- 批准号:
10366930 - 财政年份:2022
- 资助金额:
$ 32.24万 - 项目类别:
Altering the chromostasis and genome stability by modulating histone methylation
通过调节组蛋白甲基化改变染色质和基因组稳定性
- 批准号:
10696240 - 财政年份:2022
- 资助金额:
$ 32.24万 - 项目类别:
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