Thompson Lab; Department of Biochemistry and Molecular Pharmacology
Biochemistry | Cell Biology | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Molecular Biology
Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA-sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR-23b and miR-29c is suppressed by histone citrullination. Our studies demonstrate that these miRNAs directly target the mRNA of the oncogenes HMGA, IGF-1 and N-MYC, which are highly implicated in human prolactinoma/somatoprolactinoma pathogenesis. Our results are the first to define a direct role for PAD catalyzed histone citrullination in miRNA expression, which may underlie the etiology of prolactinoma and somatoprolactinoma tumors through regulation of oncogene expression.
citrullination, epigenetics, prolactinoma, miRNA, oncogenes
Rights and Permissions
Copyright © 2018, American Society for Microbiology. Publisher PDF posted after 6 months as allowed by the publisher's author rights policy at https://journals.asm.org/content/statement-author-rights.
DOI of Published Version
DeVore SB, Young CH, Li G, Sundararajan A, Ramaraj T, Mudge J, Schilkey F, Muth A, Thompson PR, Cherrington BD. 2018. Histone citrullination represses microRNA expression, resulting in increased oncogene mRNAs in somatolactotrope cells. Mol Cell Biol 38:e00084-18. Link to article on publisher's site
Molecular and cellular biology
DeVore, Stanley B; Young, Coleman H.; Li, Guangyuan; Sundararajan, Anitha; Ramaraj, Thiruvarangan; Mudge, Joann; Schilkey, Faye; Muth, Aaron; Thompson, Paul R.; and Cherrington, Brian D., "Histone citrullination represses miRNA expression resulting in increased oncogene mRNAs in somatolactotrope cells." (2018). University of Massachusetts Medical School Publications. 11.