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关键发育转变，其特征为从胎儿血红蛋白转变为成人血红蛋白（从1232转变为1222）。这种转换对于镰状细胞病和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）水平的持续升高可改善这些疾病。HbF水平的全基因组关联研究发现BCL 11 A转录抑制因子是血红蛋白开关的主要效应子。BCL 11 A抑制代表了HbF再活化的有前景的新策略。预测遗传变异会影响调控元件，从而影响BCL 11 A的表达，进而影响HbF水平。初步数据表明，BCL 11 A基因座具有离散的染色质签名。该建议测试的假设，BCL 11 A基因座是受到特定的谱系和发育阶段特定层的表观遗传调控。BCL 11 A基因座上影响HbF表达的功能性变异体可能位于调控区域内。该提案的具体目标是：1）研究BCL 11 A转录调控促进胎儿到成人发育转变的机制; 2）功能评估BCL 11 A基因座的调控元件。丹尼尔博士E.鲍尔医学博士，博士，波士顿儿童医院的研究员，概述了一个5年的职业发展计划，该计划将建立在他在儿科血液学/肿瘤学的临床背景和造血研究的研究背景之上，以使自己成为一个大型学术医疗中心儿科血液学/肿瘤学的独立研究者。在Stuart H博士的指导下，Orkin，医学博士，作为造血和表观遗传学领域公认的领导者，Bauer博士致力于将遗传和表观遗传学方法应用于生理血红蛋白开关中BCL 11 A调节的研究。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过渡。该计划理想地在波士顿儿童医院的血液学/肿瘤学部门进行，因为它在丰富，协作和支持的环境中培训医生科学家的杰出记录。在5年计划完成后，Bauer博士将开始作为独立研究者的职业生涯，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。总之，该建议旨在研究人类遗传变异和表观遗传机制，影响成人红系背景下的BCL 11 A基因座的调节。对BCL 11 A上游血红蛋白转换机制的了解增加，将为开发针对镰状细胞病和？地中海贫血此外，确定这些分子通路将有助于改善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.