LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint

被引：397

作者：

Dimitrova, Nadya ^{[1
,2
]}

Zamudio, Jesse R. ^{[1
,2
]}

Jong, Robyn M. ^{[1
,2
]}

Soukup, Dylan ^{[1
,2
]}

Resnick, Rebecca ^{[1
,2
]}

Sarma, Kavitha ^{[3
]}

Ward, Amanda J. ^{[4
]}

Raj, Arjun ^{[5
]}

Lee, Jeannie T. ^{[3
]}

Sharp, Phillip A. ^{[1
,2
]}

Jacks, Tyler ^{[1
,2
,6
]}

机构：

[1] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[2] MIT, Dept Biol, Cambridge, MA 02142 USA

[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[4] Isis Pharmaceut Inc, Carlsbad, CA 92010 USA

[5] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA

[6] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

MOLECULAR CELL | 2014年 / 54卷 / 05期

关键词：

REPRESSIVE COMPLEX 2; LONG NONCODING RNAS; P53; DIFFERENTIATION; TRANSCRIPTION; RESTORATION; PROGRESSION; SENESCENCE; PATHWAY; ERNAS;

D O I：

10.1016/j.molcel.2014.04.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：777 / 790

页数：14

共 39 条

[1] PRC2 during vertebrate organogenesis: A complex in transition [J].

Aldiri, Issam ;

Vetter, Monica L. .

DEVELOPMENTAL BIOLOGY, 2012, 367 (02) :91-99

[2] RADIATION-INDUCED CELL-CYCLE ARREST COMPROMISED BY P21 DEFICIENCY [J].

BRUGAROLAS, J ;

CHANDRASEKARAN, C ;

GORDON, JI ;

BEACH, D ;

JACKS, T ;

HANNON, GJ .

NATURE, 1995, 377 (6549) :552-557

[3] Promiscuous RNA binding by Polycomb repressive complex 2 [J].

Davidovich, Chen ;

Zheng, Leon ;

Goodrich, Karen J. ;

Cech, Thomas R. .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2013, 20 (11) :1250-U273

[4] MICE LACKING P21(C/P1/WAF1) UNDERGO NORMAL DEVELOPMENT, BUT ARE DEFECTIVE IN G1 CHECKPOINT CONTROL [J].

DENG, CX ;

ZHANG, PM ;

HARPER, JW ;

ELLEDGE, SJ ;

LEDER, P .

CELL, 1995, 82 (04) :675-684

[5] The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome [J].

Engreitz, Jesse M. ;

Pandya-Jones, Amy ;

McDonel, Patrick ;

Shishkin, Alexander ;

Sirokman, Klara ;

Surka, Christine ;

Kadri, Sabah ;

Xing, Jeffrey ;

Goren, Alon ;

Lander, Eric S. ;

Plath, Kathrin ;

Guttman, Mitchell .

SCIENCE, 2013, 341 (6147) :767-+

[6] Long non-coding RNAs: new players in cell differentiation and development [J].

Fatica, Alessandro ;

Bozzoni, Irene .

NATURE REVIEWS GENETICS, 2014, 15 (01) :7-21

[7] Stage-specific sensitivity to p53 restoration during lung cancer progression [J].

Feldser, David M. ;

Kostova, Kamena K. ;

Winslow, Monte M. ;

Taylor, Sarah E. ;

Cashman, Chris ;

Whittaker, Charles A. ;

Sanchez-Rivera, Francisco J. ;

Resnick, Rebecca ;

Bronson, Roderick ;

Hemann, Michael T. ;

Jacks, Tyler .

NATURE, 2010, 468 (7323) :572-U249

[8] Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals [J].

Guttman, Mitchell ;

Amit, Ido ;

Garber, Manuel ;

French, Courtney ;

Lin, Michael F. ;

Feldser, David ;

Huarte, Maite ;

Zuk, Or ;

Carey, Bryce W. ;

Cassady, John P. ;

Cabili, Moran N. ;

Jaenisch, Rudolf ;

Mikkelsen, Tarjei S. ;

Jacks, Tyler ;

Hacohen, Nir ;

Bernstein, Bradley E. ;

Kellis, Manolis ;

Regev, Aviv ;

Rinn, John L. ;

Lander, Eric S. .

NATURE, 2009, 458 (7235) :223-227

[9] Direct cell reprogramming is a stochastic process amenable to acceleration [J].

Hanna, Jacob ;

Saha, Krishanu ;

Pando, Bernardo ;

van Zon, Jeroen ;

Lengner, Christopher J. ;

Creyghton, Menno P. ;

van Oudenaarden, Alexander ;

Jaenisch, Rudolf .

NATURE, 2009, 462 (7273) :595-U63

[10] A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response [J].

Huarte, Maite ;

Guttman, Mitchell ;

Feldser, David ;

Garber, Manuel ;

Koziol, Magdalena J. ;

Kenzelmann-Broz, Daniela ;

Khalil, Ahmad M. ;

Zuk, Or ;

Amit, Ido ;

Rabani, Michal ;

Attardi, Laura D. ;

Regev, Aviv ;

Lander, Eric S. ;

Jacks, Tyler ;

Rinn, John L. .

CELL, 2010, 142 (03) :409-419

← 1 2 3 4 →