LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint

Nadya Dimitrova; Jesse R Zamudio; Robyn M Jong; Dylan Soukup; Rebecca Resnick; Kavitha Sarma; Amanda J Ward; Arjun Raj; Jeannie T Lee; Phillip A Sharp; Tyler Jacks

doi:10.1016/j.molcel.2014.04.025

LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint

Mol Cell. 2014 Jun 5;54(5):777-90. doi: 10.1016/j.molcel.2014.04.025. Epub 2014 May 22.

Authors

Affiliations

¹ Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
² Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
³ Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
⁴ Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, PA 19104, USA.
⁵ Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.

Abstract

The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Epigenesis, Genetic
G1 Phase Cell Cycle Checkpoints*
Mice
Mice, Knockout
Polycomb-Group Proteins / physiology*
RNA, Long Noncoding / genetics*
Transcriptional Activation
Transcriptome

LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint

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