1024 - EPIGENETIC CONTROL OF MYELOID CELL DEVELOPMENT BY THE TRANSCRIPTION FACTOR IRF8

Abstract

Differentiation of hematopoietic stem and progenitor cells to various types of blood cells is a process of establishing cell type-specific gene expression patterns. We have been investigating the mechanism of myeloid cell development from a viewpoint of gene expression control by transcription factors, particularly IRF8. In Irf8–/– mice, mononuclear phagocyte progenitors are accumulated, and these progenitors do not efficiently differentiate into monocytes (Mos) or dendritic cells (DCs) but instead, give rise to a large number of neutrophils. Accordingly, the loss of IRF8 causes immunodeficiency and chronic myeloid leukemia-like neutrophilia in mice and humans. Recently, we found that a novel 3’ enhancer is responsible for high Irf8 expression in the DC lineage. Deletion of this enhancer in vivo resulted in the loss of classical DC1s (cDC1s) and somehow surprisingly, caused a significant increase in Mo counts. Thus, the expression level of IRF8 determines the fate of myeloid progenitors; absence, low, or high expression of IRF8 promotes differentiation towards neutrophils, Mos, or DCs, respectively. We also analyzed enhancer landscape dynamics and the genome-wide behavior of IRF8 during the development of mononuclear phagocytes in vivo. While IRF8 does not immediately change the global gene expression pattern in the mononuclear phagocyte progenitors, it does establish their enhancer landscapes by cooperating or antagonizing with other transcription factors, thereby preparing for future gene expression. Furthermore, we found that IRF8 is weakly expressed in a subpopulation of lymphoid-primed multipotent progenitors and leads to early lineage specification towards cDC1s by regulating chromatin states before inducing major transcriptional changes. We are now investigating the 3D chromatin structure dynamics and the role of IRF8 during myeloid development. Collectively, these results illustrate that the epigenetic changes induced by key transcription factors such as IRF8 determine the fate of hematopoietic progenitor cells before establishing gene expression patterns.