Transcriptome and chromatin accessibility divergence during differentiation of a bipotential progenitor cell population to erythroblasts and megakaryocytes

Changes in gene expression drive differentiation along cell lineages, and shifts in gene expression are associated with alterations in chromatin accessibility reflecting activation or repression. We used deep sequencing of polyadenylated RNA to map the transcriptomes of the megakaryocyte-erythroid progenitor (MEP) and its two daughter lineages, erythroblasts (ERYs) and megakaryocytes (MEGs), in mice to reveal insights into differentiation. Transcriptome comparisons revealed that MEPs already expressed much of the MEG program while continuing to express genes associated with parallel myeloid lineages. By contrast, ERYs underwent an extensive program of gene induction along with repression of pan-hematopoietic and MEG genes. Maps of transcription factor occupancy also indicated distinct modes of regulation for the MEG and ERY programs, with MEG genes preferentially occupied by hematopoietic transcription factors in multipotent progenitors and continued occupancy postcommitment, in contrast to erythroid genes that were primarily occupied in committed ERY. Previous work revealed a surprising discordance in the clustering of MEP with other hematopoietic cell types by RNA-Seq versus chromatin states. We combined the differential expression data with chromatin accessibility across blood cell types to identify trends that contribute to this discordance. Specifically, candidate cis-regulatory elements in some ERY-specific genes were precociously actuated in the bipotential cell populations, and some other genes were expressed in both the MEP population and MEG, but their candidate cis-regulatory elements have less chromatin accessibility in MEP. This discordance in cell-type clustering by different modalities of functional genomics may reflect different contributions of subpopulations in the MEP to the particular modalities measured.