Mechanistic roles of BCL11A in globin switching and fetal hemoglobin silencing

BCL11A 在珠蛋白转换和胎儿血红蛋白沉默中的机制作用

• 批准号: 8222910
• 负责人: Jian Xu
• 金额: $ 14.91万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8222910
• 关键词: Adult; Area; BCL11A gene; Biochemical; Blood Cells; Boston; Chromatin; Collaborations; Complex; Development; Developmental Biology; Developmental Gene; Disease; Dissection; Down-Regulation; Embryo; Environment; Epigenetic Process; Erythroid; Failure; Fetal Hemoglobin; Gene Cluster; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Globin; Goals; Hematology; Hematopoiesis; Hemoglobin; Histones; Human; In Vitro; Institutes; Knock-out; Knowledge; Laboratories; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Nuclear Matrix-Associated Proteins; Patients; Pediatric Hospitals; Postdoctoral Fellow; Protein Binding; Proteins; Public Health; Recruitment Activity; Repressor Proteins; Research; Research Personnel; Research Training; Resources; Role; S cerevisiae SWI3 protein; Scientist; Severities; Sickle Cell Anemia; Site; Staging; Testing; Thalassemia; Therapeutic; Transcription Repressor/Corepressor; Transcriptional Regulation; Transgenes; Validation; Zinc Fingers; base; career; fetal; genetic association; genome-wide; in vivo; insight; interest; mortality; oncology; progenitor; research study; skills; skills training; stem cell biology; therapeutic target; transcription factor

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. PUBLIC HEALTH RELEVANCE: The 2-hemoglobin disorders, such as sickle cell anemia and 2-thalassemias, are a major public health problem. Elevated levels of fetal hemoglobin (HbF) are correlated with reduced morbidity and mortality in these diseases. There is great interest in developing approaches to induce HbF expression for therapeutic purposes. The identification and validation of BCL11A as a critical repressor of HbF expression has reinvigorated the field of globin gene regulation. In this proposal, I seek to elucidate the molecular mechanism by which BCL11A controls HbF silencing and hemoglobin switching as a means to targeted reactivation of HbF. I will systematically explore the contribution of BCL11A cooperating factors in the developmental silencing of HbF expression. The findings from these studies will advance our understanding of the role of BCL11A in HbF silencing and provide new clues for target-based therapeutics in patients with the major hemoglobin disorders.

描述（由申请人提供）：从人类胎儿（3）到成人（2）血红蛋白的发育转变代表了发育基因调控的临床重要例子。转录因子BCL11A是3-珠蛋白沉默和血红蛋白转换的新鉴定的关键调节剂。编码锌指抑制剂蛋白的BCl11a结合了人2-蛋白簇中的序列，并通过调节染色体环形成来重新配置基因座。 BCL11A控制原代人红细胞前体和携带人类2-珠簇转基因的小鼠中3-珠蛋白基因的发育沉默。因此，对BCL11A及其合作因素的重点研究应允许对所涉及的机制进行解剖，并可能揭示2种血红蛋白疾病患者的胎儿血红蛋白（HBF）重新激活的其他靶标。在该项目中，XU博士将通过与转录共抑制络合物合作并调节远程染色体相互作用来检验BCL11A沉默HBF表达的假设。具体而言，该建议的目的是：1。通过整合基因组分析来确定BCL11A的靶基因，2。在更深入的分子机制中剖析Bcl11A通过该分子机制调节3-氯宾蛋白转录和血红蛋白切换和3。探索LSD1/Corest复合物对Bcl11a介绍的贡献的贡献3-Gllobins syrencing syrencing os 3-gllobbin convery comption comption。 Jian Xu博士是波士顿儿童医院（CHB）的霍华德·休斯医学院（CHB）的博士后研究员，他提议的5年指导职业计划将在CHB的血液学/肿瘤学系实验室进行。 Xu博士的背景是分子和发育生物学，他的长期职业目标是成为具有血细胞发育和疾病基本机制专业知识的独立研究者。在转录调节，造血和干细胞生物学领域的公认领导者Orkin博士的指导下，Xu博士开发了一个研究和培训平台，这将使他能够在指导和独立的环境中获得所必需的实验技能和知识。为此，Xu博士将利用Orkin实验室的专业知识和资源，在相关研究领域获得其他技能和培训，并与专家团队建立合作。理想情况下，该计划是在波士顿儿童医院的血液学/肿瘤学系中进行的，鉴于其在富裕和协作环境中培训研究科学家的杰出记录。 公共卫生相关性：2-血红蛋白疾病，例如镰状细胞性贫血和2-甲性疾病，是一个主要的公共卫生问题。胎儿血红蛋白（HBF）水平升高与这些疾病中的发病率和死亡率降低相关。人们对开发用于治疗目的的HBF表达的方法非常感兴趣。 BCL11A作为HBF表达的关键阻遏物的鉴定和验证重新启动了球蛋白基因调节的领域。在此提案中，我试图阐明Bcl11a控制HBF沉默和血红蛋白转换的分子机制，以此作为HBF靶向重新激活的一种手段。我将系统地探索BCL11A合作因素在HBF表达的发育沉默中的贡献。这些研究的发现将提高我们对BCL11A在HBF沉默中的作用的理解，并为患有主要血红蛋白疾病患者的基于目标的治疗方法提供新的线索。