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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
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Children's Hospital Boston
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Lettre, Guillaume; Bauer, Daniel E (2016) Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. Lancet 387:2554-64
Hoban, Megan D; Bauer, Daniel E (2016) A genome editing primer for the hematologist. Blood 127:2525-35
Masuda, Takeshi; Wang, Xin; Maeda, Manami et al. (2016) Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 351:285-9
Brendel, Christian; Guda, Swaroopa; Renella, Raffaele et al. (2016) Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J Clin Invest 126:3868-3878
Henssen, Anton G; Jiang, Eileen; Zhuang, Jiali et al. (2016) Forward genetic screen of human transposase genomic rearrangements. BMC Genomics 17:548
Hoban, Megan D; Orkin, Stuart H; Bauer, Daniel E (2016) Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127:839-48
Guda, Swaroopa; Brendel, Christian; Renella, Raffaele et al. (2015) miRNA-embedded shRNAs for Lineage-specific BCL11A Knockdown and Hemoglobin F Induction. Mol Ther 23:1465-74
Anderson, Heidi; Patch, Taylor C; Reddy, Pavankumar N G et al. (2015) Hematopoietic stem cells develop in the absence of endothelial cadherin 5 expression. Blood 126:2811-20
Bauer, Daniel E; Orkin, Stuart H (2015) Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin. Curr Opin Genet Dev 33:62-70
Chung, Jacky; Bauer, Daniel E; Ghamari, Alireza et al. (2015) The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability. Sci Signal 8:ra34

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