Research accomplishments 1. We have identified an interaction between obesity and the landscape of regulatory DNA in the mouse colon. Our experiments define a pattern of enhancer utilization in the colon that resembles cancer progression and is initiated by obesity. 2. We have investigated tissue specificity to chromatin modification and gene regulation in mice. We discovered that CpG islands utilize many common regulatory features regardless of tissue type. However, each tissue fine-tunes this pattern in a specific manner. 3. We studies the impact of a specific mutation in GATA3 on properties of the protein. GATA3 is a DNA-binding transcription factor that is mutated at high frequency in breast cancer. Using a cell line (MCF7) with a tumor specific mutation, we determined that mutation leads to dramatic increase in stability of GATA3 and associated transcription factors in the face of hormonal challenge. 4. We have made significant progress in understanding the genomic distribution of NuRD complex in breast cancer cells and how this enzyme contributes to the biological program of breast cancer. 6. We have begun analysis of genome modification in an exposure model of cancer.

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U.S. National Inst of Environ Hlth Scis
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Takaku, Motoki; Grimm, Sara A; Roberts, John D et al. (2018) GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network. Nat Commun 9:1059
Duncan, Christopher G; Kondilis-Mangum, Hrisavgi D; Grimm, Sara A et al. (2018) Base-Resolution Analysis of DNA Methylation Patterns Downstream of Dnmt3a in Mouse Naïve B Cells. G3 (Bethesda) 8:805-813
Li, Ruifang; Grimm, Sara A; Mav, Deepak et al. (2018) Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer. Cell Rep 22:624-637
Takizawa, Yoshimasa; Tanaka, Hiroki; Machida, Shinichi et al. (2018) Cryo-EM structure of the nucleosome containing the ALB1 enhancer DNA sequence. Open Biol 8:
Wilczewski, Caralynn M; Hepperla, Austin J; Shimbo, Takashi et al. (2018) CHD4 and the NuRD complex directly control cardiac sarcomere formation. Proc Natl Acad Sci U S A 115:6727-6732
Li, Yin; Hamilton, Katherine J; Wang, Tianyuan et al. (2018) DNA methylation and transcriptome aberrations mediated by ER? in mouse seminal vesicles following developmental DES exposure. Proc Natl Acad Sci U S A 115:E4189-E4198
Qin, Yufeng; Roberts, John D; Grimm, Sara A et al. (2018) An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Genome Biol 19:7
Thomas, S Y; Whitehead, G S; Takaku, M et al. (2018) MyD88-dependent dendritic and epithelial cell crosstalk orchestrates immune responses to allergens. Mucosal Immunol 11:796-810
Qin, Yufeng; Wade, Paul A (2018) Crosstalk between the microbiome and epigenome: messages from bugs. J Biochem 163:105-112
Shimbo, Takashi; Dunnick, June K; Brix, Amy et al. (2017) DNA Methylation Changes in Tbx3 in a Mouse Model Exposed to Polybrominated Diphenyl Ethers. Int J Toxicol 36:229-238

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