Dynamic shifts in transcription factor occupancy drive reprogramming of gene expression during hematopoietic differentiation (LB181)

Abstract

Global views of biochemical mechanisms regulating gene expression during cell lineage commitment and maturation can be obtained by analyzing chromatin immunoprecipitation and gene expression on a genome-wide scale, enabled by massively parallel sequencing. We have conducted ChIP-seq and RNA-seq assays on cells from many informative stages of mouse hematopoiesis, ranging from multilineage progenitor cells to mature megakaryocytes and erythroblasts. We find that histone modification patterns characteristic of repressed or active chromatin are established during lineage commitment. The active chromatin forms an accessible stage on which many transcription factors change their binding patterns dynamically. Sites of binding by transcription factors, such as GATA2/1 and TAL1, change both during commitment to specific lineages and during terminal maturation. These shifts are strongly associated with changes in gene expression, allowing active proliferation in early stages and dramatic changes in morphology and function during maturation. Motif searches coupled with ChIP-seq against many transcription factors reveal co-associating proteins that help drive the dynamic binding of the key factors. Grant Funding Source: Supported by NIH grants R01DK065806 and RC2HG005573