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Single-Cell Network Analysis Identifies DDIT3 as a Nodal Lineage Regulator in Hematopoiesis.

Pina, Cristina; Teles, José LU ; Fugazza, Cristina; May, Gillian; Wang, Dapeng; Guo, Yanping; Soneji, Shamit LU ; Brown, John; Edén, Patrik LU and Ohlsson, Mattias LU , et al. (2015) In Cell Reports 11(10). p.1503-1510
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... (More)
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. (Less)
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Cell Reports
volume
11
issue
10
pages
1503 - 1510
publisher
Cell Press
external identifiers
  • pmid:26051941
  • wos:000356372100002
  • scopus:84937641068
ISSN
2211-1247
DOI
10.1016/j.celrep.2015.05.016
language
English
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yes
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228b2114-f967-4ba3-9e70-e5e4b7deba46 (old id 7487609)
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http://www.ncbi.nlm.nih.gov/pubmed/26051941?dopt=Abstract
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2015-07-07 16:46:43
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@article{228b2114-f967-4ba3-9e70-e5e4b7deba46,
  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.},
  author       = {Pina, Cristina and Teles, José and Fugazza, Cristina and May, Gillian and Wang, Dapeng and Guo, Yanping and Soneji, Shamit and Brown, John and Edén, Patrik and Ohlsson, Mattias and Peterson, Carsten and Enver, Tariq},
  issn         = {2211-1247},
  language     = {eng},
  number       = {10},
  pages        = {1503--1510},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Single-Cell Network Analysis Identifies DDIT3 as a Nodal Lineage Regulator in Hematopoiesis.},
  url          = {http://dx.doi.org/10.1016/j.celrep.2015.05.016},
  volume       = {11},
  year         = {2015},
}