This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Precisely tuned gene expression is critical for normal cellular functions as well as a variety of normal mammalian developmental processes. Histone methylation status has emerged as an important determinant of gene locus transcriptional activity. The DOT1L (Disruptor of Telomere Silencing 1-Like) histone H3 lysine- 79 (H3K79) methyltransferase has been implicated in several distinct biological processes, including positive regulation of transcription. We generated Dot1L-null mice from gene trap-targeted embryonic stem (ES) cells. Dot1L-null mice developed more slowly than wild-type embryos and died between E10.5 and E13.5. E10.5 embryos displayed a striking anemia, especially apparent in the small vessels of the yolk sac, the site of most early hematopoiesis. Further, hematopoietic progenitors from these mice displayed defective growth in response to erythroid growth factors. GATA2, a transcription factor critical for early erythropoiesis, was significantly reduced in Dot1L-deficient hematopoietic progenitors while expression of PU.1, a transcription factor that inhibits erythropoiesis and promotes myelopoiesis, was significantly increased. These data suggest a model whereby DOT1L-dependent H3K79 methylation serves as a differentiation switch during early hematopoiesis, regulating steady-state levels of GATA2 and PU.1 transcription and thus controlling the appropriate numbers of circulating erythroid and myeloid cells. This study is designed to contribute to our overall scientific goal of understanding the role for this methyltransferase in embryonic erythropoiesis. We have devised a specfic aim to examine the mechanism by which DOT1L might regulate the expression of critical genes involved in cell-fate specification during this process. The completion of this study will provide novel insight into epigenetic regulation of erythropoiesis as well as enable us to produce a substantial foundation for future work in this general area of investigation. Although the scope of the proposed work is far from comprehensive, we are confident that we will obtain data within the time allotted. These data will significantly contribute to our efforts at obtaining long-term, extramural funding for this work.

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University of Kansas
Anatomy/Cell Biology
Schools of Medicine
Kansas City
United States
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