Regulation of White Cell Development.

Abstract SCI-9

During hematopoiesis, determination of lineage and maturation to functional leukocytes depend upon cytokine-mediated changes in the transcriptional programs of progenitor and precursor cells. The classic binary branching tree of hematopoiesis now appears to be a more subtle series of gradual changes in differentiation probabilities, with competitive promotion and inhibition of lineage pathways by regulatory transcription factors such as (among others) PU.1, C/EBPα, GFI-1, EGR1/2, and NAB2 for the myeloid lineages and RUNX1, Notch-1, E2A, GATA-3, EBF, and PAX5 for lymphoid cell development. In addition, the recent discovery of regulatory non-coding RNAs (ncRNAs) has revealed another, important layer of control of hematopoiesis. The best studied members of this diverse group are the microRNAs, which often down-regulate multiple target transcripts. miRNAs involved in the regulation of myeloid development and function include miR-155, miR-223, and miR-17-19 cluster members. In addition, miR-9, miR-146a, miR-155, and miR-181a regulate the responses of immunocytes of the innate and acquired immune systems. Most recently, increasing numbers of long ncRNAs have been identified and found to regulate expression of other genes, both in cis and in trans. EGO (eosinophil granule ontogeny), a 500 base pair spliced, polyadenylated transcript regulates eosinophil granule protein gene expression. HOTAIRM1 (Hox antisense intergenic RNA, myeloid-1), a ∼500 base pair spliced polyadenylated ncRNA, affects neutrophil expression of both contiguous and distant HoxA cluster genes, as well as transcripts for CD18 integrin. Thus the control of white cell development depends not simply on a small number of key transcription factors, but rather on a complex network of interacting protein and ncRNA regulators of the transcriptional and translational programs of cell differentiation and function.