PcG protein YY1 functions in HSC self-renewal and differentiation

 描述（由申请人提供）：该提案为K 01候选人定义了一个指导性的职业发展计划，该候选人长期对造血干细胞（HSC）研究和兽医肿瘤学专业培训感兴趣。该奖项的目标是提供一个结构化的计划，将有助于潘轩博士过渡到一个兽医科学家与独立的NIH资金资源。Emery Bresnick博士将担任K 01奖的导师。他在干细胞生物学方面的专业知识和他在培训年轻科学家方面的丰富经验将对这个K 01奖非常宝贵。除了Bresnick博士的指导，这个K 01 该奖项将由一组顶级干细胞研究人员支持，包括James Thomson博士，Jing Zhang博士和Chengcheng Zhang博士。潘博士毕业于宾夕法尼亚大学的VMD-博士联合学位课程。她最近获得了威斯康星大学麦迪逊分校兽医学院医学肿瘤学助理教授的职位。由于她的职业目标是在血液学领域进行高水平的科学研究，因此K 01奖将使她能够从兽医临床医生转变为独立的兽医科学家。本项目的重点是研究Polycomb Group（PcG）蛋白Yin Yang 1（YY 1）在造血干细胞（HSC）自我更新和分化中的作用。YY 1是一种独特的和重要的哺乳动物PcG蛋白，因为它招募其他PcG成员到特定的染色体位点，导致功能上重要的组蛋白修饰模式。潘博士先前的数据显示，YY 1表达诱导骨髓移植小鼠中长期造血干细胞（LT-HSC）的扩增。在这项提案中，潘博士将使用功能获得（Aim 1a）和功能丧失（Aim 1b）研究来剖析YY 1如何控制HSC自我更新和分化的具体机制问题。她将使用一种创新的突变体（YY 1 ΔREPO），消除所有YY 1 PcG特异性功能;研究YY 1调节LT-HSC富集的潜在机制（Aim 1c）。从机制上讲，她将评估YY 1是否抑制Cdkn 2a和Cdkn 1a，这两个在HSC中建立良好的PcG调控基因座，通过招募其他PcG蛋白到这些基因座，并诱导HSC中的抑制性组蛋白修饰（目标2）。了解YY 1在HSC生物学中的功能意义和潜在机制可能为恶性血液病的治疗干预提供新的途径。

 DESCRIPTION (provided by applicant): The proposal defines a mentored career development plan for a K01 candidate with a long-standing interest in hematopoietic stem cell (HSC) research and specialty training in veterinary oncology. The goal of the award is to provide a structured program that will facilitate Dr. Xuan Pan's transition into a veterinary scientist with independent NIH funding resources. Dr. Emery Bresnick will serve as the mentor for this K01 award. His expertise in stem cell biology and his extensive experience in training young scientists will be invaluable for this K01 award. In addition to Dr. Bresnick' mentorship, this K01 award will be supported by a group of top-tier stem cell researchers including Dr. James Thomson, Dr. Jing Zhang and Dr. Chengcheng Zhang. Dr. Pan graduated from the VMD-PhD combined degree program at the University of Pennsylvania. She was recently offered a position as Assistant Professor of Medical Oncology at the University of Wisconsin-Madison School of Veterinary Medicine. As her career goal is to conduct high-level science in the field of hematology, this K01 award will allow her to transit from a veterinary clinician to an independent veterinary scientist. The focus of this project is to investigate Polycomb Group (PcG) protein Yin Yang 1 (YY1) functions in hematopoietic stem cell (HSC) self-renewal and differentiation. YY1 is a unique and crucial mammalian PcG protein, as it recruits other PcG members to specific chromosomal sites, resulting in functionally important histone modification patterns. Dr. Pan's prior data showed that YY1 expression induced an expansion of long-term hematopoietic stem cells (LT-HSCs) in bone marrow-transplanted mice. In this proposal, Dr. Pan will use gain-of-function (Aim 1a) and loss-of-function (Aim 1b) studies to dissect specific mechanistic questions regarding how YY1 controls HSC self-renewal and differentiation. She will use an innovative mutant (YY1 ΔREPO), which ablates all YY1 PcG specific functions; to study the underlying mechanisms of YY1 regulated LT-HSC enrichment (Aim 1c). Mechanistically, she will assess whether YY1 represses Cdkn2a and Cdkn1a, two well-established PcG regulatory loci in HSCs, by recruiting other PcG proteins to these loci, and inducing repressive histone modifications in HSCs (Aim 2). Understanding the functional significance and underlying mechanisms of YY1 in HSC biology may provide new avenues for possible therapeutic intervention in hematologic malignancies.