The role of chromatin structure in differentiation of hematopoietic stem cells

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 DESCRIPTION (provided by applicant): Epigenetic inheritance of the state of gene transcription relies on the conservation of the structure of chromatin through cell cycle stages during cell proliferation. Epigenetic information and structure of chromatin change during early stages of cell differentiation; this results in the activation of novel gene expression programs tht are propagated by proliferating progenitor cells. Differentiation of multipotent progenitors into myeloid or erythroid lineage-committed progenitors induces new transcriptional programs that are triggered by newly activated C/EBPα, PU.1 and GATA-1 transcription factors that bind to DNA in a sequence-specific manner. However, it is unknown whether the structure of chromatin plays a role in the initial association of these transcription factors with DNA. Using new experimental approaches to study epigenetic marking and re- assembly of proteins after DNA replication, we discovered that, compared to cytokine-treated cells, multipotent CD34+ progenitors (MPPs) are characterized by delayed maturation of chromatin following DNA replication. Based on our preliminary data, we propose that this creates a uniquely open post-replicative structure of chromatin that may explain the biological plasticity of multipotent hematopoietic progenitors. Molecularly, this plasticity may reflect facilitated association of key transcription factors, like C/EBPα, PU.1 and GATA-1 in multipotent CD34+ cells, to nascent DNA during initial stages of lineage commitment. By contrast, stem cell- enriched CD34+ cells have a more compact chromatin conformation, suggesting a model whereby changes in chromatin maturation may be essential for differentiation of hematopoietic stem cells (HSCs). We propose to test this model by investigating: i) the kinetics of induction and DNA association of transcription factors in cytokine-treated stem cell-enriched and multipotent CD34+ hematopoietic cells; ii) maturation and re- assembly of chromatin during cytokine-dependent differentiation of stem cell-enriched and multipotent CD34+ cells; iii) the role of chromatin conformation at early stages of replication for the association of transcription factors during differentiation and lineage choice of stem cell-enriched and multipotent CD34+ cells. If the proposed model of chromatin conformation `dynamics' during differentiation of HSCs and lineage commitment of MPPs is correct, these studies will have important implications for understanding the process of HSC differentiation and lineage choice in normal cells, and, perhaps, the aberrant differentiation of leukemic cells.