title: Single-Cell Network Analysis Identifies DDIT3 as a Nodal Lineage Regulator in Hematopoiesis.
abstract: We 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.
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pina
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK; Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62 Lund, Sweden.
authors.forename: José
authors.initials: J
authors.lastname: Teles
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fugazza
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: May
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Brown
authors.affiliation: Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62 Lund, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Edén
authors.affiliation: Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62 Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Ohlsson
authors.affiliation: Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62 Lund, Sweden.
authors.forename: Carsten
authors.initials: C
authors.lastname: Peterson
authors.affiliation: Stem Cell Laboratory, UCL Cancer Institute, University College London, London W1CE 6BT, UK. Electronic address: t.enver@ucl.ac.uk.
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics; D053263:Gene Regulatory Networks; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059010:Single-Cell Analysis / Q000379:methods; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism*
chemical_list: C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D051742:Transcription Factor CHOP