Pluto Bioinformatics

GSE89020: Parallel transcriptional programs driving early-starting inheritable lineage bias of myeloid, lymphoid and dendritic cells are initiated by distinct dosage of PU.1 and IRF8 in HSCs

Bulk RNA sequencing

In the traditional model of hematopoiesis, blood lineages diversify from HSCs through a sequential process of hierarchical bifurcation. Each of these bifurcation nodes comprises multipotent progenitors that are assumed to be homogeneous and equipotent in terms of their potency. The isolation of dendritic cell (DC) progenitors with either myeloid or lymphoid potency has led to the notion of convergent development, and an ongoing debate on the origin of DCs and their relationship with myeloid and lymphoid lineages. We have used a clonal assay combining with statistical modeling to quantify the yield of granulocytes (G), monocytes (M), lymphocytes (L) and three subsets of DCs from single human CD34+ progenitor cells of nine different phenotypes, and traced the potency of their individual progeny. We show that multipotent progenitors are not in fact equipotent, but instead exhibit a bias toward one specific lineage; this lineage bias is established at the HSC stage and transmitted to most progeny, with bifurcation to other lineages only occurring infrequently. Critically, these lineage biases can be correlated to lineage-specific transcriptional programs that are reinforced during division. We performed computational analysis to correlate transcriptomes and lineage composition of individual phenotype-defined progenitor cells. This enabled us to identify 32 common transcription factor (TF) candidates that interact physically and form genetic regulatory networks, with lineage-specific developmental programs initiated and reinforced based on the distinct dosage combination of these common TFs. Our analysis reveals that early expression of high levels of IRF8 and intermediate levels of PU.1 protein correlates with a bias towards CD141+ DC and plasmacytoid DC lineages in vivo, and that this pattern is inheritable from progenitors to mature cells. We have therefore arrived at a coherent model of DC development driven by parallel and inheritable programs defined by distinct dosages of TFs including PU.1 and IRF8, a developmental model that may apply to other lineages as well. SOURCE: Kang LiuLiu Lab Columbia University