title: LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Nadya
authors.initials: N
authors.lastname: Dimitrova
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Jesse R
authors.initials: JR
authors.lastname: Zamudio
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Jong
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Soukup
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Resnick
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sarma
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Ward
authors.affiliation: Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, PA 19104, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raj
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Sharp
authors.affiliation: 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.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D059585:G1 Phase Cell Cycle Checkpoints; D051379:Mice; D018345:Mice, Knockout; D063146:Polycomb-Group Proteins / Q000502:physiology*; D062085:RNA, Long Noncoding / Q000235:genetics*; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D063146:Polycomb-Group Proteins; D062085:RNA, Long Noncoding