| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2041219 | Cell Reports | 2015 | 8 Pages |
•We present a method for inferring gene regulatory networks (GRNs) from single cells•Lineage cross-antagonism is a key property of GRNs of early lineage commitment•Ddit3 is a regulatory node in erythroid lineage programming•A Ddit3-Gata2 regulatory axis antagonizes myeloid and enables erythroid programs
SummaryWe explore cell heterogeneity during spontaneous and transcription-factor-driven commitment for network inference in hematopoiesis. Since individual genes display discrete OFF states or a distribution of ON levels, we compute and combine pairwise gene associations from binary and continuous components of gene expression in single cells. Ddit3 emerges as a regulatory node with positive linkage to erythroid regulators and negative association with myeloid determinants. Ddit3 loss impairs erythroid colony output from multipotent cells, while forcing Ddit3 in granulo-monocytic progenitors (GMPs) enhances self-renewal and impedes differentiation. Network analysis of Ddit3-transduced GMPs reveals uncoupling of myeloid networks and strengthening of erythroid linkages. RNA sequencing suggests that Ddit3 acts through development or stabilization of a precursor upstream of GMPs with inherent Meg-E potential. The enrichment of Gata2 target genes in Ddit3-dependent transcriptional responses suggests that Ddit3 functions in an erythroid transcriptional network nucleated by Gata2.
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