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

Research output: Contribution to journalArticlepeer-review

37 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 languageEnglish (US)
Pages (from-to)856-871
Number of pages16
JournalMolecular Endocrinology
Volume30
Issue number8
DOIs
StatePublished - Aug 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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