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Nature DOI:10.1038/nature13990

Dissecting neural differentiation regulatory networks through epigenetic footprinting.

Publication TypeJournal Article
Year of Publication2015
AuthorsZiller, MJ, Edri, R, Yaffe, Y, Donaghey, J, Pop, R, Mallard, W, Issner, R, Gifford, CA, Goren, A, Xing, J, Gu, H, Cacchiarelli, D, Tsankov, AM, Epstein, C, Rinn, JL, Mikkelsen, TS, Kohlbacher, O, Gnirke, A, Bernstein, BE, Elkabetz, Y, Meissner, A
Date Published2015 Feb 19
KeywordsBinding Sites, Cell Differentiation, Cell Lineage, Embryonic Stem Cells, Epigenesis, Genetic, Epigenomics, Humans, Neural Stem Cells, Reproducibility of Results, RNA, Small Interfering, Transcription Factors, Transcription, Genetic

Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system. Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line. Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.


Alternate JournalNature
PubMed ID25533951
PubMed Central IDPMC4336237
Grant ListU54 HG006991 / HG / NHGRI NIH HHS / United States
F32 DK095537 / DK / NIDDK NIH HHS / United States
P01 GM099117 / GM / NIGMS NIH HHS / United States
U01ES017155 / ES / NIEHS NIH HHS / United States
HG006911 / HG / NHGRI NIH HHS / United States
P01GM099117 / GM / NIGMS NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States