The developmental switch from human fetal (3) to adult (2) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a newly identified critical regulator of 3-globin silencing and hemoglobin switching. BCL11A, which encodes a zinc-finger repressor protein, binds to sequences within the human 2-globin cluster and reconfigures the locus by modulating chromosomal loop formation. BCL11A controls the developmental silencing of 3-globin genes in primary human erythroid precursors and in mice carrying a human 2-globin cluster transgene. Therefore, focused study of BCL11A and its cooperating factors should allow dissection of the mechanisms involved and may reveal additional targets for reactivation of fetal hemoglobin (HbF) in patients with 2-hemoglobin disorders. In this project, Dr. Xu will test the hypothesis that BCL11A silences HbF expression through cooperating with transcriptional co-repressor complexes and modulating long-range chromosomal interactions. Specifically, this proposal will aim to: 1. Determine target genes of BCL11A by integrative genomic analysis, 2. Dissect in greater depth the molecular mechanisms by which BCL11A modulates 3-globin transcription and hemoglobin switching and 3. Explore the contribution of LSD1/CoREST complexes to BCL11A-mediated silencing of 3-globin expression. Dr. Jian Xu is a postdoctoral fellow at the Howard Hughes Medical Institute, Children's Hospital Boston (CHB) and his proposed 5-year mentored career plan will be performed in the laboratory of Dr. Stuart Orkin in the Division of Hematology/Oncology at CHB. Dr. Xu's background is in molecular and developmental biology, and his long-term career goal is to become an independent investigator with expertise in basic mechanisms of blood cell development and disorders. Under the mentorship of Dr. Orkin, a recognized leader in the fields of transcriptional regulation, hematopoiesis, and stem cell biology, Dr. Xu has developed a research and training platform that will allow him to acquire the experimental skills and knowledge necessary to be productive in both a mentored and independent setting. To accomplish this, Dr. Xu will take advantage of the expertise and resources of the Orkin lab, acquire additional skills and training in relevant research areas, and establish collaboration with a team of experts. The plan is ideally carried out in the Division of Hematology/Oncology at Children's Hospital Boston, given its distinguished record for training research scientists in a rich and collaborative environment.
The 2-hemoglobin disorders; such as sickle cell anemia and 2-thalassemias; are a major public health problem. Elevated levels of fetal hemoglobin (HbF) are correlated with reduced morbidity and mortality in these diseases. There is great interest in developing approaches to induce HbF expression for therapeutic purposes. The identification and validation of BCL11A as a critical repressor of HbF expression has reinvigorated the field of globin gene regulation. In this proposal; I seek to elucidate the molecular mechanism by which BCL11A controls HbF silencing and hemoglobin switching as a means to targeted reactivation of HbF. I will systematically explore the contribution of BCL11A cooperating factors in the developmental silencing of HbF expression. The findings from these studies will advance our understanding of the role of BCL11A in HbF silencing and provide new clues for target-based therapeutics in patients with the major hemoglobin disorders.
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