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CRISPR-Cas9 Screens Reveal Genes Regulating a G0-Like State in Human Neural Progenitors

76 Pages Posted: 25 Jul 2018 Sneak Peek Status: Review Complete

See all articles by Heather M. Feldman

Heather M. Feldman

Fred Hutchinson Cancer Research Center - Human Biology Division

Chad M. Toledo

Fred Hutchinson Cancer Research Center - Human Biology Division

Sonali Arora

Fred Hutchinson Cancer Research Center - Human Biology Division

Pia Hoellerbauer

Fred Hutchinson Cancer Research Center - Human Biology Division

Philip Corrin

Fred Hutchinson Cancer Research Center - Human Biology Division

Lucas Carter

Fred Hutchinson Cancer Research Center - Human Biology Division

Megan Kufeld

Fred Hutchinson Cancer Research Center - Human Biology Division

Hamid Bolouri

Fred Hutchinson Cancer Research Center - Human Biology Division

Ryan Basom

Fred Hutchinson Cancer Research Center - Genomics and Bioinformatics Shared Resources

Jeffrey Delrow

Fred Hutchinson Cancer Research Center - Genomics and Bioinformatics Shared Resources

Joshua Meier

Massachusetts Institute of Technology (MIT) - Department of Brain and Cognitive Sciences

Feng Zhang

Massachusetts Institute of Technology (MIT) - Department of Brain and Cognitive Sciences

José L. McFaline-Figueroa

University of Washington - Department of Genome Sciences

Cole Trapnell

University of Washington - Department of Genome Sciences

Steven M. Pollard

University of Edinburgh - Edinburgh Cancer Research UK Centre

Christopher L. Plaisier

Arizona State University (ASU) - School of Biological and Health Systems Engineering

Patrick Paddison

Fred Hutchinson Cancer Research Center - Human Biology Division

More...

Abstract

The coordination of developmental potential and proliferation in stem and progenitor cells is essential for mammalian development and tissue homeostasis. To better understand this coordination in human neural progenitor cells (hNPCs), we performed CRISPR-Cas9 screens and identified genes that limit their expansion. These screens revealed that knockout of growth-limiting genes, including CREBBP, NF2, PTPN14, TAOK1, or TP53, caused increased hNPC expansion via skipping of a transient G0-like state, accompanied by transcriptional reprogramming of G1 subpopulations. Hallmarks of the G0-like state included expression of genes associated with quiescent neural stem cells and neural development and molecular features found in quiescent cells (e.g., hypophosphorylated Rb, CDK2low activity, and p27high). Further, G0-skip genes act through both distinct and convergent downstream effectors, including cell cycle, Hippo-YAP, and novel targets. The results suggest that hNPC expansion is constrained by a transient G0-like state, regulated by multiple pathways, that facilitates retention of neurodevelopmental identity.

Suggested Citation

Feldman, Heather M. and Toledo, Chad M. and Arora, Sonali and Hoellerbauer, Pia and Corrin, Philip and Carter, Lucas and Kufeld, Megan and Bolouri, Hamid and Basom, Ryan and Delrow, Jeffrey and Meier, Joshua and Zhang, Feng and McFaline-Figueroa, José L. and Trapnell, Cole and Pollard, Steven M. and Plaisier, Christopher L. and Paddison, Patrick, CRISPR-Cas9 Screens Reveal Genes Regulating a G0-Like State in Human Neural Progenitors (2018). Available at SSRN: https://ssrn.com/abstract=3219283 or http://dx.doi.org/10.2139/ssrn.3219283
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Heather M. Feldman

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Chad M. Toledo

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Sonali Arora

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Pia Hoellerbauer

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Philip Corrin

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Lucas Carter

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Megan Kufeld

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Hamid Bolouri

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Ryan Basom

Fred Hutchinson Cancer Research Center - Genomics and Bioinformatics Shared Resources

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Jeffrey Delrow

Fred Hutchinson Cancer Research Center - Genomics and Bioinformatics Shared Resources

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Joshua Meier

Massachusetts Institute of Technology (MIT) - Department of Brain and Cognitive Sciences

43 Vassar Street
Cambridge, MA 02139
United States

Feng Zhang

Massachusetts Institute of Technology (MIT) - Department of Brain and Cognitive Sciences

43 Vassar Street
Cambridge, MA 02139
United States

José L. McFaline-Figueroa

University of Washington - Department of Genome Sciences

Seattle, WA 98195
United States

Cole Trapnell

University of Washington - Department of Genome Sciences

Seattle, WA 98195
United States

Steven M. Pollard

University of Edinburgh - Edinburgh Cancer Research UK Centre

Edinburgh
United Kingdom

Christopher L. Plaisier

Arizona State University (ASU) - School of Biological and Health Systems Engineering

Farmer Building 440G PO Box 872011
Tempe, AZ 85287
United States

Patrick Paddison (Contact Author)

Fred Hutchinson Cancer Research Center - Human Biology Division

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

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