Mechanistic roles of BCL11A in globin switching and fetal hemoglobin silencing

描述（由申请人提供）：从人类胎儿(3)到成人(2)血红蛋白的发育转换代表了发育基因调控的临床重要例子。转录因子BCL11A是新发现的3-珠蛋白沉默和血红蛋白转换的关键调节因子。BCL11A编码锌指抑制蛋白，与人类2-珠蛋白簇中的序列结合，并通过调节染色体环的形成来重新配置位点。BCL11A在原发性人红系前体和携带人2-珠蛋白簇转基因的小鼠中控制3-珠蛋白基因的发育沉默。因此，对BCL11A及其协同因子的重点研究应该能够解剖相关机制，并可能揭示2-血红蛋白疾病患者胎儿血红蛋白（HbF）再激活的其他靶点。在这个项目中，徐博士将验证BCL11A通过与转录共抑制复合物合作和调节远程染色体相互作用来沉默HbF表达的假设。具体而言，本提案旨在：1。通过整合基因组分析确定BCL11A的靶基因；深入剖析BCL11A调节3-珠蛋白转录和血红蛋白转换的分子机制。探讨LSD1/CoREST复合物在bcl11a介导的3-球蛋白表达沉默中的作用。徐健博士是波士顿儿童医院（CHB）霍华德休斯医学研究所的博士后，他提出的5年指导职业规划将在CHB血液学/肿瘤学部Stuart Orkin博士的实验室进行。他的背景是分子和发育生物学，他的长期职业目标是成为一名独立的研究者，在血细胞发育和疾病的基本机制方面具有专长。在转录调节，造血和干细胞生物学领域公认的领导者Dr. Orkin的指导下，Xu博士开发了一个研究和培训平台，使他能够获得在指导和独立环境中生产所需的实验技能和知识。为了实现这一目标，徐博士将利用Orkin实验室的专业知识和资源，获得相关研究领域的额外技能和培训，并与专家团队建立合作关系。鉴于波士顿儿童医院血液学/肿瘤科在丰富和协作环境中培训研究科学家的杰出记录，该计划理想地在该科实施。

DESCRIPTION (provided by applicant): The developmental switch from human fetal (3) to adult (2) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a newly identified critical regulator of 3-globin silencing and hemoglobin switching. BCL11A, which encodes a zinc-finger repressor protein, binds to sequences within the human 2-globin cluster and reconfigures the locus by modulating chromosomal loop formation. BCL11A controls the developmental silencing of 3-globin genes in primary human erythroid precursors and in mice carrying a human 2-globin cluster transgene. Therefore, focused study of BCL11A and its cooperating factors should allow dissection of the mechanisms involved and may reveal additional targets for reactivation of fetal hemoglobin (HbF) in patients with 2-hemoglobin disorders. In this project, Dr. Xu will test the hypothesis that BCL11A silences HbF expression through cooperating with transcriptional co-repressor complexes and modulating long-range chromosomal interactions. Specifically, this proposal will aim to: 1. Determine target genes of BCL11A by integrative genomic analysis, 2. Dissect in greater depth the molecular mechanisms by which BCL11A modulates 3-globin transcription and hemoglobin switching and 3. Explore the contribution of LSD1/CoREST complexes to BCL11A-mediated silencing of 3-globin expression. Dr. Jian Xu is a postdoctoral fellow at the Howard Hughes Medical Institute, Children's Hospital Boston (CHB) and his proposed 5-year mentored career plan will be performed in the laboratory of Dr. Stuart Orkin in the Division of Hematology/Oncology at CHB. Dr. Xu's background is in molecular and developmental biology, and his long-term career goal is to become an independent investigator with expertise in basic mechanisms of blood cell development and disorders. Under the mentorship of Dr. Orkin, a recognized leader in the fields of transcriptional regulation, hematopoiesis, and stem cell biology, Dr. Xu has developed a research and training platform that will allow him to acquire the experimental skills and knowledge necessary to be productive in both a mentored and independent setting. To accomplish this, Dr. Xu will take advantage of the expertise and resources of the Orkin lab, acquire additional skills and training in relevant research areas, and establish collaboration with a team of experts. The plan is ideally carried out in the Division of Hematology/Oncology at Children's Hospital Boston, given its distinguished record for training research scientists in a rich and collaborative environment.