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Role of PAD2 in hormone receptor target gene activation

This project is using state-of-the-art technologies to improve our understanding of the fundamental mechanisms by which hormone receptors (HRs) gain access to their DNA binding element within nucleosomes and activate transcription. The histone N-terminal tails represent major impediments to HR-nucleosomal DNA binding because they protrude from the core particle and interact with the underlying DNA via their charged arginine and lysine residues. To help overcome this obstacle, HRs, such as the estrogen receptor (ER), recruit histone acetyltransferases (HATs) to neutralize histone tail lysine residues, thus weakening histone-DNA interactions. The mechanisms by which HRs neutralize histone tail arginine residues have, until recently, remained unknown. Peptidylarginine deiminase (PAD) enzymes convert arginine residues to neutrally charged citrulline in a process known as deimination or citrullination. We have previously reported that PAD2 interacts with ER and that PAD2-mediated deimination of histone H3 arginine 26 (H3R26Cit) enhances ERs ability to bind to target promoter DNA. Our more recent ChIP-Seq study demonstrates that the H3R26Cit modification is essentially absent from breast cancer cells prior to hormone stimulation and then rapidly accumulates at over 30,000 ER binding sites within 5 min of estrogen treatment. Our genome-wide analysis also found that the peak structure and location of this modification virtually mirrors that of the ER across the ER cistrome. We hypothesize that ER recruits HATs and PAD2 to estrogen response element (ERE)-containing nucleosomes and these co-factors then neutralize lysine and arginine residues on the histone H3 tails via acetylation and deimination to weaken histone H3 tail-nucleosomal DNA interactions and stabilize ER-ERE binding. Outcomes from these  ongoing studies will help to elucidate the mechanisms of HR signaling and catalyze innovative new cancer therapies for breast cancer.