During FY2001 we built upon key observations that we made concerning the mechanisms by which steroid receptors activate transcription within breast cancer cells. We demonstrated that proteins involved in the manipulation of chromatin structure, chromatin remodeling machines, represent the key components in the cascade of events that results in the activation of the genetic program in human breast cancer cells. We have made significant advances in understanding the nature of the cellular response to prolonged glucocorticoid exposure. Our studies revealed that there is a profound reduction in the level of phosphorylated histone H1 that is directly linked to the cessation of transcription. The mechanism that underpins this result is the inhibition of the key cell cycle regulator CDK2 in response to glucocorticoid. In congruence with our hypothesis that understanding chromatin structure is vital to understanding gene regulation these events take place only in the context of chromatin. We continued to analyze the activity of the glucocorticoid receptor within breast and osteosarcoma cancer cells that differ in the expression of components of the chromatin remodeling machines. These cells display an altered response to a variety of clinically important hormone antagonist and will be useful in evaluating various anti-hormone strategies in breast cancer. In addition they are a unique resource to evaluate and characterize the impact of a number of environmental agents in human cells. To this end we have continued to develop methodologies that allow us to look at protein-DNA interactions within living cells, in vivo footprinting, as well as changes at the control regions of specific genes within living cell, chromatin immunoprecipitation (CHIP) assays.

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National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
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Singh, Ajeet Pratap; Foley, Julie; Tandon, Arpit et al. (2017) A role for BRG1 in the regulation of genes required for development of the lymphatic system. Oncotarget 8:54925-54938
Singh, Ajeet P; Foley, Julie F; Rubino, Mark et al. (2016) Brg1 Enables Rapid Growth of the Early Embryo by Suppressing Genes That Regulate Apoptosis and Cell Growth Arrest. Mol Cell Biol 36:1990-2010
Lavender, Christopher A; Cannady, Kimberly R; Hoffman, Jackson A et al. (2016) Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters. PLoS Genet 12:e1006224
Takaku, Motoki; Grimm, Sara A; Shimbo, Takashi et al. (2016) GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biol 17:36
Yang, Jun; Bennett, Brian D; Luo, Shujun et al. (2015) LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells. Mol Cell Biol 35:3225-43
Wade, Staton L; Langer, Lee F; Ward, James M et al. (2015) MiRNA-Mediated Regulation of the SWI/SNF Chromatin Remodeling Complex Controls Pluripotency and Endodermal Differentiation in Human ESCs. Stem Cells 33:2925-35
Zhang, Xiaoli; Li, Bing; Li, Wenguo et al. (2014) Transcriptional repression by the BRG1-SWI/SNF complex affects the pluripotency of human embryonic stem cells. Stem Cell Reports 3:460-74
Singh, Ajeet Pratap; Archer, Trevor K (2014) Analysis of the SWI/SNF chromatin-remodeling complex during early heart development and BAF250a repression cardiac gene transcription during P19 cell differentiation. Nucleic Acids Res 42:2958-75
Rana, Ritu; Coulter, Sherry; Kinyamu, Harriet et al. (2013) RBCK1, an E3 ubiquitin ligase, interacts with and ubiquinates the human pregnane X receptor. Drug Metab Dispos 41:398-405
Singh, Ajeet Pratap; Cummings, Connie A; Mishina, Yuji et al. (2013) SOX8 regulates permeability of the blood-testes barrier that affects adult male fertility in the mouse. Biol Reprod 88:133

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