Exposure to environmental chemicals during specific, susceptible periods of fetal development can reprogram target tissues and increase disease incidence later in life. Xenoestrogens are a class of endocrine disrupters found throughout our environment that are capable of reprogramming a number of tissues, including the female reproductive tract. Previous studies from our laboratory demonstrated that perinatal xenoestrogen exposure reprograms estrogen-responsive genes in the myometrium and elevates leiomyoma incidence in rats. The mechanisms underlying reprogramming and subsequent tumorigenesis in uterine tissue following xenoestrogen exposure are unknown. However, interaction between estrogenic signaling and epigenetic regulation of gene expression such as changes in histone and DMA methylation is the probable cause of this developmental programming. Recent studies indicate that histone methylation is a precursor for the establishment of permanent epigenetic states within the genome. In addition, exciting new data demonstrate that cell signaling pathways, which can be activated by estrogen via non-genomic signaling, modulate the activity of histone methyltransferase (HMT) enzymes. Based on this information we hypothesize that xenoestrogens alter chromatin structure via aberrant modulation of histone methylation, causing permanent reprogramming of genes. To address this hypothesis, we propose the following Specific Aims:
Specific Aim 1) Determine if estrogen receptor signaling alters HMT activity.
Specific Aim 2) Determine if estrogens induce gene-specific changes in histone methylation.
Specific Aim 3) Determine if the ability to alter HMT activity and induce gene-specific methyl marks is shared across broad classes of xenoestrogens.
The proposed studies will be used to carefully dissect the impact of estrogen signaling on HMTs using chromatin immunoprecipitation, HMT activity assays, transfection of constitutively active and dominant negative signaling proteins, and site-directed mutagenesis. The goal of this application is to investigate a novel mechanism of action for environmental estrogens.
| 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 |
| Bredfeldt, Tiffany G; Greathouse, K Leigh; Safe, Stephen H et al. (2010) Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol 24:993-1006 |
