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Science. 2017 Jan 6;355(6320). pii: aah7111. doi: 10.1126/science.aah7111. Epub 2016 Dec 15.

CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells.

Liu SJ1,2, Horlbeck MA3,4,5,6, Cho SW7, Birk HS1,2, Malatesta M1,2, He D1,2, Attenello FJ1,2, Villalta JE3,4,5,6, Cho MY3,4,5,6, Chen Y3,4,5,6, Mandegar MA3, Olvera MP3, Gilbert LA3,4,5,6, Conklin BR3,8,9, Chang HY7, Weissman JS10,4,5,6, Lim DA11,2,12.

Author information

  • 1Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
  • 2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
  • 3Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
  • 4Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
  • 5California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA 94143, USA.
  • 6Center for RNA Systems Biology, University of California, San Francisco, CA 94143, USA.
  • 7Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
  • 8Deparment of Medicine, University of California, San Francisco, CA 94143, USA.
  • 9Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.
  • 10Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA. daniel.lim@ucsf.edu jonathan.weissman@ucsf.edu.
  • 11Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA. daniel.lim@ucsf.edu jonathan.weissman@ucsf.edu.
  • 12San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.

Abstract

The human genome produces thousands of long noncoding RNAs (lncRNAs)-transcripts >200 nucleotides long that do not encode proteins. Although critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. We developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in seven diverse cell lines, including six transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth-modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type-specific manner. These data underscore the functional importance and cell type specificity of many lncRNAs.

PMID:
27980086
DOI:
10.1126/science.aah7111
[PubMed - in process]
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