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Nature. 2015 Feb 19;518(7539):355-359. doi: 10.1038/nature13990. Epub 2014 Dec 24.

Dissecting neural differentiation regulatory networks through epigenetic footprinting.

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Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, 6997801, Israel.
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Center for Systems Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Applied Bioinformatics, Center for Bioinformatics and Quantitative Biology Center, University of Tübingen, Tübingen, Germany.
Contributed equally


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.

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