Transcriptional Regulation in Normal and Malignant Hematopoiesis

Abstract SCI-28

Lineage commitment should involve selective and temporally-regulated expression of essential genes. In multi- or oligo-potent progenitors, the expression of oligo-lineage-affiliated genes is primed: oligo-lineage genes are co-expressed prior to the commitment at the single cell level, and once lineage fate is decided, genes of irrelevant lineages are immediately downregulated. For example, single common myeloid progenitors (CMP) co-express both granulocyte/monocyte-affiliated and megakaryocyte/erythroid-affiliated genes. The priming of these lineage-restricted genes could be dependent also upon the priming of lineage-specific transcription factors. Consistent with this hypothesis, a population with potent CMP activity that co-express both PU.1 (myeloid) and GATA-1 (erythroid) transcription factors was newly identified by using mice having PU.1 and GATA-1 reporters. In downstream of such “priming” stage, the order of expression as well as the level of expression of multiple transcription factors plays a critical role in reading-out specific lineages. The precise regulation of transcription factors should be critical to maintain hematopoietic homeostasis, and the deregulation of transcription factor expression could induce leukemic transformation. To understand the regulation machinery upstream of transcription factors, we are currently attempting to model an epigenetic landscape in hematopoietic development. Genome-wide analysis of histone positioning revealed that a histone variant marks hematopoietic transcription factors and other lineage-related genes prior to commitment, and therefore the variant can predict the actively-transcribed region in a later stage of hematopoiesis. For example, in hematopoietic stem cells, the histone marking was observed broadly in genes-related to myelo-erythroid and lymphoid genes, while in committed progenitors, it was restricted to specific lineages such as myeloid, erythroid and/or lymphoid genes. These results suggest that the genome marking by a histone variant should be a primary event for initiating lineage commitment.