Epigenetic regulation of BCL11A in the hemoglobin switch

BCL11A 在血红蛋白开关中的表观遗传调控

• 批准号: 8224974
• 负责人: Daniel Evan Bauer
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224974
• 关键词: Academic Medical Centers; Adult; Advisory Committees; Affect; Alleles; Applied Genetics; BCL11A gene; Biochemical; Biological Assay; Birth; Boston; Cell Fate Control; Cells; ChIP-seq; Chromatin; Chromosomes; Clinical; Code; DNA Methylation; DNA Resequencing; Data; Deoxyribonuclease I; Development; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; EP300 gene; Enhancers; Environment; Epigenetic Process; Erythroblasts; Erythroid; Erythroid Cells; Fetal Hemoglobin; Functional RNA; GATA1 gene; Genes; Genetic Variation; Globin; Goals; Growth; Hematology; Hematopoiesis; Hematopoietic; Hemoglobin; Human; Human Genetics; Hypersensitivity; In Vitro; Inborn Genetic Diseases; Knowledge; Longevity; Maps; Mediator of activation protein; Mentorship; Modeling; Molecular; Mutagenesis; Mutation; Nucleic Acid Regulatory Sequences; Pathway interactions; Pattern; Pediatric Hematology/Oncology; Pediatric Hospitals; Physicians; Physiological; Quality of life; RNA; Regulation; Regulatory Element; Reporter; Research; Research Personnel; Residual state; Resolution; Scientist; Sickle Cell Anemia; Single Nucleotide Polymorphism; Staging; System; Testing; Thalassemia; Time; Training; Transcript; Transcription Repressor/Corepressor; Transcriptional Regulation; Transgenic Mice; Variant; career; career development; derepression; design; fetal; genome wide association study; human GATA1 protein; improved; in vivo; new therapeutic target; novel strategies; novel therapeutics; oncology; research study; therapeutic target

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. PUBLIC HEALTH RELEVANCE: Sickle cell disease and 2-thalassemia are common inherited disorders of adult hemoglobin that result in both reduced quality of life and shortened lifespan. Modifying mutations in a gene called BCL11A can ameliorate these diseases by reactivation of residual fetal hemoglobin. This proposal aims to better understand how BCL11A is turned on, with the ultimate goal of rationally designing new therapies to reactivate fetal hemoglobin in sickle cell disease and 2-thalassemia.

描述（由申请人提供）：在出生时期，在红细胞细胞中发生了关键的发育过渡，其特征是从胎儿转变为成人血红蛋白（从1232年到1222年）。由于胎儿血红蛋白（HBF）持续升高可以改善这些疾病，因此这种转换对镰状细胞疾病和2-助理症具有关键的病理生理意义。 HBF水平的全基因组关联研究导致发现BCL11A转录阻遏物是血红蛋白开关的主要效应子。 BCL11A抑制是HBF重新激活的一种有希望的新型策略。预计遗传变异会影响影响BCL11A表达的调节元素，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。该建议检验了Bcl11a基因座的假设受到表观遗传调节的特异性和发育阶段特异性层的约束。影响HBF表达的BCL11A基因座的功能变异可能存在于调节区域内。该提案的具体目的是：1）研究促进胎儿到成群发展过渡的BCL11A转录调节机制； 2）在BCL11A基因座的功能评估调节元素。波士顿儿童医院的研究员丹尼尔·E·鲍尔（Daniel E.在造血和表观遗传学领域的公认领导者Stuart H. Orkin博士的指导下，Bauer博士试图将遗传和表观遗传学方法应用于生理血红蛋白开关中BCL11A调节的研究。该领域的国际认可专家咨询委员会将监督他向独立的过渡。理想情况下，该计划是在波士顿儿童医院的血液学/肿瘤学部门进行的，鉴于其在丰富，协作和支持性的环境中培训医师科学家的杰出记录。在完成5年计划时，鲍尔博士将以独立调查员的身份启动职业，重点是使用血红蛋白转换作为模型的造血细胞命运控制的表观遗传学。总而言之，该提案旨在研究影响成人红细胞环境中BCL11A基因座调节的人类遗传变异和表观遗传机制。对BCL11A上游血红蛋白开关的基础机制的知识越来越多，将为靶向HBF重新激活的新型治疗剂的发展和thalassalassia。此外，识别这些分子途径将有助于改善对谱系规范和个体发育的基本理解。 公共卫生相关性：镰状细胞疾病和2-甲性疾病是成年血红蛋白的常见遗传疾病，既导致生活质量降低和寿命缩短。在称为BCL11A的基因中修饰突变可以通过重新激活残留胎儿血红蛋白来改善这些疾病。该提案旨在更好地了解BCL11A的打开方式，其最终目标是合理设计新疗法以重新激活镰状细胞病和2-甲性疾病中的胎儿血红蛋白。