Epigenetic regulation of BCL11A in the hemoglobin switch

描述（由申请人提供）：红细胞在出生前后发生一个关键的发育转变，其特征是从胎儿血红蛋白到成人血红蛋白的转换（从1232到1222）。这种开关对于镰状细胞病和2-地中海贫血具有重要的病理生理意义，因为胎儿血红蛋白（HbF）水平的持续升高可以改善这些疾病。HbF水平的全基因组关联研究发现BCL11A转录抑制因子是血红蛋白开关的主要效应因子。抑制BCL11A是一种很有前景的HbF再激活新策略。预计遗传变异会影响影响BCL11A表达的调控元件，从而影响HbF水平。初步数据表明，BCL11A基因座具有离散的染色质特征。这一建议验证了BCL11A基因座受谱系特异性和发育阶段特异性表观遗传调控层的假设。影响HbF表达的BCL11A基因座的功能变异可能位于调控区域内。本课题的具体目的是：1)研究BCL11A转录调控促进胎儿向成人发育转变的机制；2)对BCL11A位点的调控元件进行功能评价。Daniel E. Bauer博士，医学博士，波士顿儿童医院研究员，概述了一个5年的职业发展计划，该计划将建立在他在儿童血液学/肿瘤学的临床背景和造血研究的研究背景上，使他成为一个大型学术医疗中心儿童血液学/肿瘤学的独立调查员。在造血和表观遗传学领域公认的领导者Stuart H. Orkin博士的指导下，Bauer博士寻求应用遗传学和表观遗传学方法来研究BCL11A在生生性血红蛋白开关中的调节。一个由该领域国际公认专家组成的咨询委员会将监督他向独立过渡。鉴于波士顿儿童医院血液学/肿瘤科在丰富、协作和支持的环境中培训医生科学家的杰出记录，该计划在该部门进行是理想的。在五年计划完成后，Bauer博士将开始作为独立研究员的职业生涯，专注于以血红蛋白转换为模型的造血细胞命运控制的表观遗传学。综上所述，本研究旨在研究成人红系背景下影响BCL11A基因座调控的人类遗传变异和表观遗传机制。对BCL11A上游血红蛋白开关机制的进一步了解，将为镰状细胞病和地中海贫血中针对HbF再激活的新疗法的开发提供信息。此外，识别这些分子途径将有助于提高对谱系规范和个体发生的基本理解。

DESCRIPTION (provided by applicant): A key developmental transition occurs in erythroid cells around the time of birth characterized by the switch from fetal to adult hemoglobin (from 1232 to 1222). This switch is of critical pathophysiologic significance for sickle cell disease and 2-thalassemia, as persistent elevations of fetal hemoglobin (HbF) levels ameliorate these diseases. Genome-wide association studies of HbF levels led to the discovery of the BCL11A transcriptional repressor as a major effector of the hemoglobin switch. BCL11A inhibition represents a promising novel strategy for HbF reactivation. Genetic variation is predicted to affect regulatory elements influencing the expression of BCL11A, and thereby HbF level. Preliminary data indicate that the BCL11A locus possesses discrete chromatin signatures. This proposal tests the hypothesis that the BCL11A locus is subject to lineage-specific and developmental stage-specific layers of epigenetic regulation. Functional variants at the BCL11A locus that affect HbF expression are likely to reside within regulatory regions. The specific aims of this proposal are to: 1) investigate mechanisms of BCL11A transcriptional regulation promoting the fetal-to-adult developmental transition; and 2) functionally evaluate regulatory elements at the BCL11A locus. Dr. Daniel E. Bauer, M.D., Ph.D., a fellow at Children's Hospital Boston, has outlined a 5-year career development plan that will build upon his clinical background in pediatric hematology/oncology and research background in the study of hematopoiesis to establish himself as an independent investigator in pediatric hematology/oncology at a large academic medical center. Under the mentorship of Dr. Stuart H. Orkin, M.D., a recognized leader in the fields of hematopoiesis and epigenetics, Dr. Bauer seeks to apply genetic and epigenetic approaches to the study of BCL11A regulation in the physiologic hemoglobin switch. An Advisory Committee of internationally recognized experts in the field will oversee his transition to independence. This plan is ideally carried out in the Division of Hematology/Oncology at Children's Hospital Boston, given its distinguished record of training physician-scientists in a rich, collaborative, and supportive environment. At the completion of the 5-year plan, Dr. Bauer will launch a career as an independent investigator with a focus on the epigenetics of hematopoietic cell fate control using hemoglobin switching as a model. In summary, this proposal aims to investigate human genetic variation and epigenetic mechanisms that influence the regulation of the BCL11A locus within the adult erythroid context. Increased knowledge of mechanisms underlying the hemoglobin switch upstream of BCL11A will inform the development of novel therapeutics targeting HbF reactivation in sickle cell disease and ?-thalassemia. Furthermore, identifying these molecular pathways will contribute to an improved basic understanding of lineage specification and ontogeny.