||Thursday, 10 April 2014, 17:30～
||Seminar-shitsu 1, IDAC Research building 7F
||Genomic Dissection of Normal and Malignant Hematopoiesis
||Prof. Emery Bresnick
||University of Wisconsin
||Hozumi Motohashi Dept. Gene Expression Regulation (ex:8550)
||Master transcriptional regulators establish and maintain complex genetic networks that seamlessly orchestrate transitions from stem cells to progenitors and to differentiated cell progeny. Given the crucial function of master regulators in this process, it is intrinsically interesting to ask how factors and signals control their expression and activity. We have addressed this problem in the context of GATA-2, an essential regulator of hematopoiesis, which was known to be an important determinant of the genesis and/or function of hematopoietic stem cells (HSCs). Our approach has involved establishing the transcription factor and chromatin landscape of the endogenous Gata2 locus, which has revealed multiple prospective regulatory regions predicted to be involved in activating GATA-2 expression at the earliest stages of hematopoiesis or repressing its expression at subsequent developmental stages. We have generated mutant mouse strains lacking these prospective regulatory regions and assessed their importance in a developmentally dynamic context in vivo. These studies have led to the discovery of a cis-regulatory element that endows hemogenic endothelium with the capacity to form HSCs and is mutated in a human immunodeficiency that progresses to myelodysplasia and acute myeloid leukemia as well as additional cis-regulatory elements with unique biological and mechanistic attributes. I will discuss this long-term effort and how it constitutes the basis for our HSC cistrome hypothesis. In addition, I will provide an overview of our efforts to prioritize and analyze 797 prospective cis-regulatory elements that emerged from principles derived from the GATA-2 work. These elements are expected to yield key determinants of the genesis and function of HSCs in physiological and pathophysiological contexts that will not likely emerge from conventional experimental strategies.