SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

Ken Tajima; Toshifumi Yae; Sarah Javaid; Oliver Tam; Valentine Comaills; Robert Morris; Ben S. Wittner; Mingzhu Liu; Amanda Engstrom; Fumiyuki Takahashi; Joshua C. Black; Sridhar Ramaswamy; Toshihiro Shioda; Molly Hammell; Daniel A. Haber; Johnathan R. Whetstine; Shyamala Maheswaran

doi:10.1038/ncomms9257

SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

Ken Tajima, Toshifumi Yae, Sarah Javaid, Oliver Tam, Valentine Comaills, Robert Morris, Ben S. Wittner, Mingzhu Liu, Amanda Engstrom, Fumiyuki Takahashi, Joshua C. Black, Sridhar Ramaswamy, Toshihiro Shioda, Molly Hammell, Daniel A. Haber, Johnathan R. Whetstine, Shyamala Maheswaran

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41 Scopus citations

Abstract

Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.

Original language	English
Article number	8257
Pages (from-to)	8257
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9257
State	Published - Sep 23 2015

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Tajima, K., Yae, T., Javaid, S., Tam, O., Comaills, V., Morris, R., Wittner, B. S., Liu, M., Engstrom, A., Takahashi, F., Black, J. C., Ramaswamy, S., Shioda, T., Hammell, M., Haber, D. A., Whetstine, J. R., & Maheswaran, S. (2015). SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes. Nature Communications, 6, 8257. Article 8257. https://doi.org/10.1038/ncomms9257

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title = "SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes",

abstract = "Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.",

author = "Ken Tajima and Toshifumi Yae and Sarah Javaid and Oliver Tam and Valentine Comaills and Robert Morris and Wittner, {Ben S.} and Mingzhu Liu and Amanda Engstrom and Fumiyuki Takahashi and Black, {Joshua C.} and Sridhar Ramaswamy and Toshihiro Shioda and Molly Hammell and Haber, {Daniel A.} and Whetstine, {Johnathan R.} and Shyamala Maheswaran",

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doi = "10.1038/ncomms9257",

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Tajima, K, Yae, T, Javaid, S, Tam, O, Comaills, V, Morris, R, Wittner, BS, Liu, M, Engstrom, A, Takahashi, F, Black, JC, Ramaswamy, S, Shioda, T, Hammell, M, Haber, DA, Whetstine, JR & Maheswaran, S 2015, 'SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes', Nature Communications, vol. 6, 8257, pp. 8257. https://doi.org/10.1038/ncomms9257

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T1 - SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

AU - Tajima, Ken

AU - Yae, Toshifumi

AU - Javaid, Sarah

AU - Tam, Oliver

AU - Comaills, Valentine

AU - Morris, Robert

AU - Wittner, Ben S.

AU - Liu, Mingzhu

AU - Engstrom, Amanda

AU - Takahashi, Fumiyuki

AU - Black, Joshua C.

AU - Ramaswamy, Sridhar

AU - Shioda, Toshihiro

AU - Hammell, Molly

AU - Haber, Daniel A.

AU - Whetstine, Johnathan R.

AU - Maheswaran, Shyamala

PY - 2015/9/23

Y1 - 2015/9/23

N2 - Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.

AB - Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.

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VL - 6

SP - 8257

JO - Nature Communications

JF - Nature Communications

M1 - 8257

ER -

SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

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