This section is interested in transcription factors that regulate the development of the immune system. We previously isolated ICSBP/IRF-8, a DNA specific transcription factor expressed in hematopoietic cells and showed that it regulates the development of bone marrow progenitor cells to generate macrophages and granulocytes. We also showed that introduction of ICSBP rescues normal growth and differentiation of these cells in ICSBP-null progenitors. It can also rescue the development and maturation of dendritic cells (DCs), cells important for host defense, which are profoundly defective in ICSBP-null mice. We found that a critical target gene controlled by ICSBP is IL-12p40, a cytokine expressed in macrophages and DCs and is critical for establishing innate immunity. Although IL-12p40 is not produced in ICSBP-/- macrophages and DCs, reintroduction of ICSBP can fully restore the cytokine production. By DNA microarray analysis with 15,000 murine cDNAs, we have begun to identify additional target genes that are directly regulated by ICSBP. About 50 known and unknown genes are found to be either increased or decreased following ICSBP expression, some of which are known to be important for macrophage/DC function. Studies of target promoters and the chromatin status of ICSBP-null cells suggest that this factor regulates gene expression not only by controlling target promoters, but regulating the activity of chromatin. We study the role of chromatin from another perspective, and characterize a bromodomain protein Brd4. Brd4 is a novel member of the conserved BET family, that contains a motif indicative of interaction with chromatin. We showed that it associates with mitotic chromosomes, consistent with a strong affinity for chromatin. Recent FRET and FLIP analyses suggest that Brd4 and a related protein interact with acetylated histones in living cells. By an over-expression strategy, Brd4 is found to regulate cell growth. We show that this growth regulation is partly attributed to the interaction of Brd4 with RFC, conserved DNA replication machinery, which occurs through the bromodomain. Further elucidation of the role of this factor is pursued by conditional knock-out and antisense/RNAi approaches.
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