Exposure of cells or tissues to environmental stressors during critical periods of development can permanently reprogram normal physiological responses to increase susceptibility to disease later in life, a process termed developmental reprogramming. Developmental reprogramming is thought to occur via disruption of the epigenome, and is now appreciated to increase risk in adulthood for metabolic diseases, including obesity, diabetes, cardiovascular disease, and cancer. We were the first to identify non-genomic (or more accurately pre-genomic) signaling as a direct mechanism for endocrine disrupting chemicals (EDCs) to disrupt the epigenetic machinery and induce developmental reprogramming. Activation of kinases in pre-genomic signaling pathways that phosphorylate readers, writers and erasers is extremely attractive as a central mechanism for environmental stressors to engage the cell's epigenetic machinery. However, tremendous knowledge gaps remain in our understanding of how the epigenomic machinery is disrupted by pre-genomic signaling during developmental reprogramming. We do not know: 1) Which kinases/pre-genomic signaling pathways beyond PI3K/AKT are activated by 'obesogens' in the liver (or other tissues); 2) Which epigenomic programmers are targeted by these kinases or how phosphorylation (or other PTMs) modifies their activity (up or down); nor 3) Which specific epigenetic 'marks' placed on reprogrammed genes are altered to change gene expression and increase susceptibility to obesity (or other diseases) in adulthood. The goal of this application i to fill these knowledge gaps with a detailed mechanistic understanding of how EDCs utilize pre-genomic signaling to disrupt the epigenome, and to better understand how this developmental reprogramming alters metabolic 'set-points' in the liver to promote obesity.
Exposure to endocrine disrupting chemicals (EDCs) in early life can confer complex and long-lasting pathophysiological consequences later in life; including obesity. We hypothesize that EDCs induce this developmental reprogramming by engaging cell signaling pathways that post-translationally modify epigenetic ''readers; writers; and erasers''; and nuclear hormone receptor coregulators responsible for these epigenomic marks. Here; we will determine how four EDCs; relevant to human exposure; disrupt the normal function of epigenomic programmers and how this perturbation reprograms genes regulating metabolic ''set-points'' in the liver to promote obesity.
|Treviño, Lindsey S; Katz, Tiffany A (2018) Endocrine Disruptors and Developmental Origins of Nonalcoholic Fatty Liver Disease. Endocrinology 159:20-31|
|Cheng, Donghang; Vemulapalli, Vidyasiri; Lu, Yue et al. (2018) CARM1 methylates MED12 to regulate its RNA-binding ability. Life Sci Alliance 1:e201800117|
|Szafran, Adam T; Stossi, Fabio; Mancini, Maureen G et al. (2017) Characterizing properties of non-estrogenic substituted bisphenol analogs using high throughput microscopy and image analysis. PLoS One 12:e0180141|
|Foulds, Charles E; Treviño, Lindsey S; York, Brian et al. (2017) Endocrine-disrupting chemicals and fatty liver disease. Nat Rev Endocrinol 13:445-457|
|Walker, Cheryl Lyn (2016) Minireview: Epigenomic Plasticity and Vulnerability to EDC Exposures. Mol Endocrinol 30:848-55|
|Park, In Young; Powell, Reid T; Tripathi, Durga Nand et al. (2016) Dual Chromatin and Cytoskeletal Remodeling by SETD2. Cell 166:950-962|
|Wang, Quan; Trevino, Lindsey S; Wong, Rebecca Lee Yean et al. (2016) Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk. Mol Endocrinol 30:856-71|
|Szafran, Adam T; Mancini, Maureen G; Nickerson, Jeffrey A et al. (2016) Use of HCA in subproteome-immunization and screening of hybridoma supernatants to define distinct antibody binding patterns. Methods 96:75-84|
|Hartig, Sean M; Bader, David A; Abadie, Kathleen V et al. (2015) Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes. Mol Endocrinol 29:1320-33|
|Treviño, 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|
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