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Toward Understanding the Role of the Polycomb Complex in Skin Control

了解 Polycomb 复合物在皮肤控制中的作用

基本信息

批准号：
10686047
负责人：
Elena Ezhkova
金额：
$ 44.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686047
关键词：
Ablation Acceleration Adult Aging Animals Biochemical Biological Process ChIP-seq Chromatin Complex Cues Data Disease Down-Regulation Equilibrium Experimental Genetics Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Growth Hair Hair follicle structure Homeostasis Human Knockout Mice Lead Life Malignant Neoplasms Mediating Molecular Multipotent Stem Cells Mus Mutate Natural regeneration Organism PRC1 Protein Phenotype Play Polycomb Process Production Proliferating Regulation Regulator Genes Reporting Repression Rest Role Signal Transduction Skin Skin Cancer System Testing Traction Transcription Coactivator WNT Signaling Pathway bone morphogenetic protein receptors comparison control daughter cell derepression epithelial stem cell experimental study gene repression human disease in vivo inhibitor insight loss of function multipotent cell novel premature skin disorder stem cells transcriptome sequencing

项目摘要

Project Summary Hair follicle stem cells (HFSCs) have the unique ability to generate new hair follicles throughout the lifetime of an organism. When the growth of a new hair follicle occurs, HFSCs are activated; they proliferate to fuel the production of a new follicle and quickly return to quiescence. While the means by which this transition between quiescence and activation is regulated remain elusive, identification of these processes is critical, because abnormal HFSC activation has implications in hair loss, aging, and cancer. Polycomb repressive complexes (PRC) 1 and 2 are chromatin transcriptional regulators that are essential for maintaining stem cell identity. By performing loss-of-function studies, we showed that loss of PRC1 in HFSCs results in premature activation of HFSCs and the induction of hair growth, whereas loss of PRC2 leads to a prolonged HFSC quiescence and delayed hair growth. These data show the critical and opposing roles of Polycomb complexes in regulation of HFSC quiescence. This is an intriguing observation because PRC1 and PRC2 are thought to act together, and, in most systems, the loss of either PRC1 or PRC2 results in identical phenotypes. We hypothesize that PRC1 and PRC2 maintain the delicate balance of quiescence and activation, but their mechanism of action is different than what was previously reported. In Aim 1, we will determine the molecular mechanisms by which PRC2 fine-tunes HFSC quiescence. By performing RNA-seq, we identified that Wnt inhibitors Notum and Sfrp2, and BMP receptor Bmpr1b are upregulated in the PRC2-null HFSC. Because Wnt inhibition and Bmp activation are known to promote HFSC quiescence, we hypothesize that expression of these genes leads to delayed HFSC activation. Here, we will analyze whether expression of Notum, Sfrp2, and/or Bmpr1b promotes HFSC quiescence and recapitulates the PRC2-null phenotype. In Aim 2, we will examine cooperation between repressive PRC1 and PRC2 functions in control of HFSCs. Our recent studies showed that PRC1 and PRC2 have additive gene-repressive roles and that only loss of both leads to complete de-repression of PRC1/2 target genes. Here, we will ablate repressive functions of both PRC1 and PRC2 complexes in HFSCs, analyze the phenotype, and determine molecular mechanisms of PRC1/2 control of HFSCs. In Aim 3, we will examine noncanonical gene-activating roles of PRC1 in promoting HFSC quiescence. Because loss of PRC1 and PRC2 show opposing phenotypes, respectively, we hypothesize that PRC1 functions independently of PRC2 to promote the expression of genes that influence HFSC quiescence. Here, we will identify genes that are under the control of PRC1 in HFSCs by performing RNA-seq and ChIP-seq studies and test whether downregulation of said genes results in precocious HFSC activation. The completion of these studies will define how Polycomb-mediated gene regulation fine-tunes the delicate balance between quiescence and activation in HFSCs.

项目摘要毛囊干细胞（HFSC）具有在一生中生成新毛囊的独特能力一个有机体。当新毛囊生长时，HFSC被激活;它们增殖以刺激毛囊生长。产生一个新的卵泡，并迅速恢复静止。虽然这种过渡的方式，静止和激活的调节仍然难以捉摸，这些过程的识别是至关重要的，因为异常的HFSC活化与脱发、衰老和癌症有关。多梳抑制复合物（PRC）1和2是染色质转录调节因子，来维持干细胞的特性通过进行功能丧失的研究，我们发现， HFSC导致HFSC的过早激活和毛发生长的诱导，而PRC 2的缺失导致延长HFSC静止期和延迟毛发生长。这些数据表明，多梳复合物对HFSC静止期的调控。这是一个有趣的观察，因为PRC 1和 PRC 2被认为是一起起作用的，并且在大多数系统中，PRC 1或PRC 2的丢失导致相同的表型我们假设PRC 1和PRC 2维持了静止和激活的微妙平衡，但它们的作用机制与以前报道的不同。在目标1中，我们将确定PRC 2微调HFSC静止的分子机制。通过通过RNA-seq，我们发现Wnt抑制剂Notum和Sfrp 2以及BMP受体Bmpr 1b是在PRC 2缺失的HFSC中上调。因为已知Wnt抑制和Bmp活化促进HFSC 静止期，我们假设这些基因的表达导致HFSC激活延迟。在这里，我们将分析Notum、Sfrp 2和/或Bmpr 1b的表达是否促进HFSC静止和重演 PRC 2-null表型。在目标2中，我们将考察专制的PRC 1和PRC 2之间的合作。控制HFSC的功能。我们最近的研究表明，PRC 1和PRC 2具有加性基因抑制作用，只有两者的缺失才会导致PRC 1/2靶基因的完全去阻遏。在这里，我们将消融 PRC 1和PRC 2复合物在HFSC中的抑制功能，分析表型，并确定 PRC 1/2控制HFSCs的分子机制。在目标3中，我们将研究非经典基因激活 PRC 1在促进HFSC静止中的作用。因为PRC 1和PRC 2的缺失显示相反的表型，因此，我们假设PRC 1独立于PRC 2发挥作用，促进基因的表达，影响HFSC静止。在这里，我们将通过以下方法鉴定HFSC中受PRC 1控制的基因：进行RNA-seq和ChIP-seq研究，并测试所述基因的下调是否导致 HFSC过早激活。这些研究的完成将确定Polycomb介导的基因调节微调HFSC中静止和激活之间的微妙平衡。