Epigenetic regulation of BCL11A in the hemoglobin switch

描述(由申请人提供)：出生前后红系细胞发生了一个关键的发育转变，其特征是从胎儿血红蛋白转变为成人血红蛋白(从1232到1222)。这种转变对镰状细胞病和2-地中海贫血具有重要的病理生理学意义，因为胎儿血红蛋白(HBF)水平的持续升高可以改善这些疾病。对HBF水平的全基因组关联研究导致了BCL11A转录抑制物作为血红蛋白开关的主要效应器的发现。抑制BCL11A代表了一种很有前途的HBF重新激活的新策略。据预测，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基因座受制于谱系特定和发育阶段特定的表观遗传调控层的假设。BCL11A基因座上影响HBF表达的功能变异很可能位于调节区内。这一建议的具体目的是：1)研究BCL11A转录调控促进胎儿向成人发育转变的机制；2)从功能上评估BCL11A基因座的调控元件。丹尼尔·鲍尔博士，医学博士，博士，波士顿儿童医院研究员，概述了一项为期5年的职业发展计划，该计划将以他在儿科血液学/肿瘤学的临床背景和造血研究的研究背景为基础，确立自己作为一家大型学术医学中心儿科血液学/肿瘤学的独立研究员的地位。在造血和表观遗传学领域公认的领导者、医学博士斯图尔特·H·奥尔金的指导下，鲍尔博士试图将遗传学和表观遗传学方法应用于BCL11A在生理性血红蛋白开关中的调节研究。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的过渡。鉴于波士顿儿童医院在丰富、协作和支持的环境中培训内科科学家的杰出记录，该计划在波士顿儿童医院的血液科/肿瘤科实施是理想的。在这个五年计划完成后，鲍尔博士将以独立研究员的身份开始他的职业生涯，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，这项建议旨在研究在成人红系背景下影响BCL11A基因调控的人类遗传变异和表观遗传机制。对BCL11A上游血红蛋白开关潜在机制的了解增加，将为针对镰状细胞病和β-地中海贫血的HBF重新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改进对谱系规范和个体发育的基本理解。

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.