Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk

Quan Wang; Lindsey S. Trevino; Rebecca Lee Yean Wong; Mario Medvedovic; Jing Chen; Shuk Mei Ho; Jianjun Shen; Charles E. Foulds; Cristian Coarfa; Bert W. O’Malley; Ali Shilatifard; Cheryl L. Walker

doi:10.1210/me.2015-1310

Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk

Quan Wang, Lindsey S. Trevino, Rebecca Lee Yean Wong, Mario Medvedovic, Jing Chen, Shuk Mei Ho, Jianjun Shen, Charles E. Foulds, Cristian Coarfa, Bert W. O’Malley, Ali Shilatifard, Cheryl L. Walker^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

66 Scopus citations

Abstract

Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase; (PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer.

Original language	English (US)
Pages (from-to)	856-871
Number of pages	16
Journal	Molecular Endocrinology
Volume	30
Issue number	8
DOIs	https://doi.org/10.1210/me.2015-1310
State	Published - Aug 2016

Funding

This work was supported by National Institute of Environmental Health Sciences Grants RC2ES018789, P30ES023512, ES023206 and U01 ES026719; the Cancer Prevention Research Institute of Texas (CPRIT) Grant RP120855; and the Welch Foundation Grant BE-0023 (Houston, TX) (to C.L.W.). This study also made use of the MD Anderson Science Park Next Generation Sequencing Core, supported by the CPRIT Core Facility Support Award RP120348, and the Baylor College of Medicine Advanced Technology Core Bioinformatics Core, supported by the CPRIT Core Facility Support Award RP120092 and a National Cancer Institute Shared Resources Award P30CA125123.

ASJC Scopus subject areas

Endocrinology
Molecular Biology

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10.1210/me.2015-1310

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title = "Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk",

abstract = "Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase; (PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer.",

author = "Quan Wang and Trevino, {Lindsey S.} and Wong, {Rebecca Lee Yean} and Mario Medvedovic and Jing Chen and Ho, {Shuk Mei} and Jianjun Shen and Foulds, {Charles E.} and Cristian Coarfa and O{\textquoteright}Malley, {Bert W.} and Ali Shilatifard and Walker, {Cheryl L.}",

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doi = "10.1210/me.2015-1310",

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AU - Chen, Jing

AU - Ho, Shuk Mei

AU - Shen, Jianjun

AU - Foulds, Charles E.

AU - Coarfa, Cristian

AU - O’Malley, Bert W.

AU - Shilatifard, Ali

AU - Walker, Cheryl L.

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Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk

Abstract

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UN SDGs

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