Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters

Tiffany Hung; Yulei Wang; Michael F. Lin; Ashley K. Koegel; Yojiro Kotake; Gavin D. Grant; Hugo M. Horlings; Nilay Shah; Christopher Umbricht; Pei Wang; Yu Wang; Benjamin Kong; Anita Langerød; Anne Lise Børresen-Dale; Seung K. Kim; Marc Van De Vijver; Saraswati Sukumar; Michael L. Whitfield; Manolis Kellis; Yue Xiong; David J. Wong; Howard Y. Chang

doi:10.1038/ng.848

Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters

Tiffany Hung, Yulei Wang, Michael F. Lin, Ashley K. Koegel, Yojiro Kotake, Gavin D. Grant, Hugo M. Horlings, Nilay Shah, Christopher Umbricht, Pei Wang, Yu Wang, Benjamin Kong, Anita Langerød, Anne Lise Børresen-Dale, Seung K. Kim, Marc Van De Vijver, Saraswati Sukumar, Michael L. Whitfield, Manolis Kellis, Yue XiongDavid J. Wong, Howard Y. Chang

Research output: Contribution to journal › Article › peer-review

1040 Scopus citations

Abstract

Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53-dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell-growth control.

Original language	English (US)
Pages (from-to)	621-629
Number of pages	9
Journal	Nature Genetics
Volume	43
Issue number	7
DOIs	https://doi.org/10.1038/ng.848
State	Published - Jul 2011
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Hung, T., Wang, Y., Lin, M. F., Koegel, A. K., Kotake, Y., Grant, G. D., Horlings, H. M., Shah, N., Umbricht, C., Wang, P., Wang, Y., Kong, B., Langerød, A., Børresen-Dale, A. L., Kim, S. K., Van De Vijver, M., Sukumar, S., Whitfield, M. L., Kellis, M., ... Chang, H. Y. (2011). Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nature Genetics, 43(7), 621-629. https://doi.org/10.1038/ng.848

Hung, T, Wang, Y, Lin, MF, Koegel, AK, Kotake, Y, Grant, GD, Horlings, HM, Shah, N, Umbricht, C, Wang, P, Wang, Y, Kong, B, Langerød, A, Børresen-Dale, AL, Kim, SK, Van De Vijver, M, Sukumar, S, Whitfield, ML, Kellis, M, Xiong, Y, Wong, DJ & Chang, HY 2011, 'Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters', Nature Genetics, vol. 43, no. 7, pp. 621-629. https://doi.org/10.1038/ng.848

@article{14bc7e02794e4c4d881e048d3ee1df13,

title = "Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters",

abstract = "Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53-dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell-growth control.",

author = "Tiffany Hung and Yulei Wang and Lin, {Michael F.} and Koegel, {Ashley K.} and Yojiro Kotake and Grant, {Gavin D.} and Horlings, {Hugo M.} and Nilay Shah and Christopher Umbricht and Pei Wang and Yu Wang and Benjamin Kong and Anita Langer{\o}d and B{\o}rresen-Dale, {Anne Lise} and Kim, {Seung K.} and {Van De Vijver}, Marc and Saraswati Sukumar and Whitfield, {Michael L.} and Manolis Kellis and Yue Xiong and Wong, {David J.} and Chang, {Howard Y.}",

note = "Funding Information: We thank J. Rinn, M. Guttman and A. Regev for discussions, L. Attardi for careful reading of the manuscript and P. Khavari for reagents. Y.W., B.K. and Yu Wang are employees of Life Technologies. This work was supported by grants from the US National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (K08-AR054615 to D.J.W.), NIH/National Cancer Institute (NCI) (R01-CA118750 to H.Y.C. and R01-CA130795 to M.L.W.), the Juvenile Diabetes Research Foundation (S.K.K. and H.Y.C.) and the American Cancer Society (H.Y.C.). H.Y.C. is an Early Career Scientist of the Howard Hughes Medical Institute. T.H. is supported by the Stanford Graduate Fellowship, the National Science Foundation (NSF) Graduate Research Fellowship and the Department of Defense (DoD) National Defense Science & Engineering Graduate Fellowship (NDSEG).",

year = "2011",

month = jul,

doi = "10.1038/ng.848",

language = "English (US)",

volume = "43",

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T1 - Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters

AU - Hung, Tiffany

AU - Wang, Yulei

AU - Lin, Michael F.

AU - Koegel, Ashley K.

AU - Kotake, Yojiro

AU - Grant, Gavin D.

AU - Horlings, Hugo M.

AU - Shah, Nilay

AU - Umbricht, Christopher

AU - Wang, Pei

AU - Wang, Yu

AU - Kong, Benjamin

AU - Langerød, Anita

AU - Børresen-Dale, Anne Lise

AU - Kim, Seung K.

AU - Van De Vijver, Marc

AU - Sukumar, Saraswati

AU - Whitfield, Michael L.

AU - Kellis, Manolis

AU - Xiong, Yue

AU - Wong, David J.

AU - Chang, Howard Y.

N1 - Funding Information: We thank J. Rinn, M. Guttman and A. Regev for discussions, L. Attardi for careful reading of the manuscript and P. Khavari for reagents. Y.W., B.K. and Yu Wang are employees of Life Technologies. This work was supported by grants from the US National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (K08-AR054615 to D.J.W.), NIH/National Cancer Institute (NCI) (R01-CA118750 to H.Y.C. and R01-CA130795 to M.L.W.), the Juvenile Diabetes Research Foundation (S.K.K. and H.Y.C.) and the American Cancer Society (H.Y.C.). H.Y.C. is an Early Career Scientist of the Howard Hughes Medical Institute. T.H. is supported by the Stanford Graduate Fellowship, the National Science Foundation (NSF) Graduate Research Fellowship and the Department of Defense (DoD) National Defense Science & Engineering Graduate Fellowship (NDSEG).

PY - 2011/7

Y1 - 2011/7

N2 - Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53-dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell-growth control.

AB - Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53-dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell-growth control.

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Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters

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