Inappropriate exposure to environmental agents during critical, sensitive periods of development can reprogram target tissues via epigenetic mechanisms to increase the risk for disease later in adult life. The reproductive tract is particularly sensitive to this type of developmental programming in response to xenoestrogen exposure, a major class of endocrine disrupting chemicals that are ubiquitously present in our environment. We have recently shown that developmental programming following neonatal xenoestrogen exposure can increase the risk of developing hormone-dependent leiomyoma by increasing the responsiveness to hormone of estrogen-responsive genes in the myometrium. Although the epigenetic mechanism(s) responsible for developmental programming are unknown, recent data indicate that one type of epigenetic modification, histone methylation, is altered in response to activation of PI3K signaling via phosphorylation of histone methyltransferases by AKT. Since estrogens can activate PI3K via nongenomic signaling, we hypothesize that xenoestrogens, via activation of cell signaling pathways, can modify the activity of histone methyltransferases, leading to epigenetic alterations in histone methylation patterns that contribute to developmental programming in the uterus. To test this hypothesis, we propose the following Specific Aims:
Specific Aim 1 : Test the hypothesis that estrogen-activation of cell signaling results in changes in histone modifications that alter gene expression.
Specific Aim 2 : Determine if phosphorylation of methyltransferases by AKT or ERK is responsible for changes in histone modifications that occur in response to estrogens.
Specific Aim 3 : Determine the contribution of histone modifications to developmental programming of gene expression in the uterus. These studies will explore activation of cell signaling as a novel mechanism by which histone methyltransferase activity can be modulated by estrogens, resulting in epigenetic alterations in histone methylation patterns. In addition, they will determine if changes in histone methylation induced by neonatal exposure to xenoestrogens are heritable and contribute to developmental programming by modulating gene expression in adult animals. Project Narrative Uterine leiomyoma are the most common gynecologic tumor of women and they have a tremendous negative affect on the health of millions of women in the US. Surprisingly, we know very little about what causes these tumors, although hormones, including environmental estrogens, have been implicated in the etiology of this disease. We propose that a potential mechanism by which environmental estrogens may contribute to the development of these tumors is through developmental programming. In this application we will test the hypothesis that during development of the uterus, exposure to environmental estrogens reprograms gene expression in the myometrium to predispose to the development of these tumors later in life. The mechanism that we propose for this reprogramming is the activation of nongenomic signaling pathways to modulate the activity of histone methyltransferases and induce alterations in epigenetic patterns of histone methylation.
|Park, In Young; Powell, Reid T; Tripathi, Durga Nand et al. (2016) Dual Chromatin and Cytoskeletal Remodeling by SETD2. Cell 166:950-62|
|TreviÃ±o, Lindsey S; Wang, Quan; Walker, Cheryl L (2015) Hypothesis: Activation of rapid signaling by environmental estrogens and epigenetic reprogramming in breast cancer. Reprod Toxicol 54:136-40|
|TreviÃ±o, Lindsey S; Wang, Quan; Walker, Cheryl L (2015) Phosphorylation of epigenetic ""readers, writers and erasers"": Implications for developmental reprogramming and the epigenetic basis for health and disease. Prog Biophys Mol Biol 118:8-13|
|Wong, Rebecca Lee Yean; Walker, Cheryl Lyn (2013) Molecular pathways: environmental estrogens activate nongenomic signaling to developmentally reprogram the epigenome. Clin Cancer Res 19:3732-7|
|Greathouse, K Leigh; Bredfeldt, Tiffany; Everitt, Jeffrey I et al. (2012) Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 10:546-57|
|Walker, Cheryl Lyn; Ho, Shuk-mei (2012) Developmental reprogramming of cancer susceptibility. Nat Rev Cancer 12:479-86|
|Walker, Cheryl Lyn (2011) Epigenomic reprogramming of the developing reproductive tract and disease susceptibility in adulthood. Birth Defects Res A Clin Mol Teratol 91:666-71|
|Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39|
|McCampbell, Adrienne S; Harris, Heather A; Crabtree, Judy S et al. (2010) Loss of inhibitory insulin receptor substrate-1 phosphorylation is an early event in mammalian target of rapamycin-dependent endometrial hyperplasia and carcinoma. Cancer Prev Res (Phila) 3:290-300|
|McCampbell, Adrienne S; Broaddus, Russell R; Walker, Cheryl L (2010) Loss of inhibitory insulin receptor substrate-1 phosphorylation: An early event in endometrial hyperplasia and progression to carcinoma. Cell Cycle 9:2698-9|
Showing the most recent 10 out of 36 publications