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PMID: 24857549 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Molecular cell ·Vol. 54 ·No. 5 ·2014-06-05 ·Pages 777-90

Dimitrova N, Zamudio JR, Jong RM, Soukup D, Resnick R, Sarma K, Ward AJ, Raj A, Lee JT, Sharp PA, Jacks T

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.

MeSH Terms
Animals Cell Proliferation Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21/genetics,metabolism Epigenesis, Genetic G1 Phase Cell Cycle Checkpoints Mice Mice, Knockout Polycomb-Group Proteins/physiology RNA, Long Noncoding/genetics Transcriptional Activation Transcriptome
Chemicals
Cyclin-Dependent Kinase Inhibitor p21 Polycomb-Group Proteins RNA, Long Noncoding
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Dimitrova Nadya
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Zamudio Jesse R
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Jong Robyn M
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Soukup Dylan
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Resnick Rebecca
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Sarma Kavitha
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Ward Amanda J
Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Raj Arjun
Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, PA 19104, USA.
Lee Jeannie T
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Sharp Phillip A
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Jacks Tyler
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: [email protected].
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2014.04.025
Email
[email protected]
Published
2014-06-05
Epub
2014-00-22
Pages
777-90
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC4103188
Subset
IM
Grants
NCI NIH HHS · P01 CA042063 · United States
NCI NIH HHS · P30 CA014051 · United States
NIH HHS · DP2 OD008514 · United States
NCI NIH HHS · R01 CA133404 · United States
Howard Hughes Medical Institute · United States
Databases
GEO
GSE52958
External Links
PubMed source DOI: 10.1016/j.molcel.2014.04.025 PMC Full Text View journal details
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