M. A. Bender, MD, PhD, is attending physician at Seattle Children’s Hospital and director of Odessa Brown Comprehensive Sickle Cell Clinic; he is an associate professor at the University of Washington School of Medicine and has a research lab at the Fred Hutchinson Cancer Research Center (FHCRC).
Clinically, Bender has a long-standing commitment to hemoglobinopathies with an emphasis on sickle cell disease, and special emphasis on patient education, community outreach and access to health care. He acts as a consultant to the state newborn screening program regarding hemoglobinopathies, providing advice to the state, community physicians and families. Bender has worked with the Puget Sound Blood Center’s Rare Blood Groups program to increase the number of minority donors by overcoming cultural barriers and improving education and information services, and he received the American Society of Hematology’s Champion for Advocacy award. He is member of the NIH Sickle Cell Disease Advisory Committee.
His research focuses on regulation of the chromatin structure in vivo, using the beta-globin locus as a model. Bender is working on multiple projects, ranging from developing new techniques to analyze chromatin structure, to establishing a statewide collaborative to provide better support for patients, families, practitioners and community members affected by sickle cell disease. In order to test hypotheses’ as to how chromatin structure is regulated he has generated mice with deletions of DNase I hypersensitive sites (HSs) that mark putative regulatory regions of the beta-globin locus. The largest of these deletes the control region (LCR), and results in changes in chromatin structure, expression, sub-nuclear localization and timing of DNA replication, raising the question of how these attributes are linked and coordinated. The most prominent model for beta-globin gene activation proposes that the LCR and HSs flanking interact to form an “active chromatin hub” essential for high-level expression. Systematic deletion of components of this hub suggest that this model is in fact not correct, and raising the questions 1) what is the function of these highly conserved regions, 2) what is necessary for activation of the locus and 3) how these mutations affect nuclear localization, chromatin structure and replication timing and how these attributes are linked. For example, the nuclear periphery is associated with silenced genes, while the nuclear interior is associated with active gene expression. Notably, with erythroid differentiation beta-globin expression increases and is associated with re-localization from the periphery to the central nucleoplasm, begging the question of if expression leads to re-localization, re-localization leads to activation of expression, or if these processes are regulated independently. How these processes change with differentiation and the role of cis-acting elements is being determined.