RelB/p52-mediated NF-κB signaling alters histone acetylation to increase the abundance of corticotropin-releasing hormone in human placenta

• Published in: Science signaling Vol. 8; no. 391; p. ra85
• Main Authors: Di Stefano, Valeria, Wang, Bingbing, Parobchak, Nataliya, Roche, Natalie, Rosen, Todd
• Format: Journal Article
• Language: English
• Published: United States 25.08.2015
• Subjects: Acetylation - drug effects; Adolescent; Adult; Corticotropin-Releasing Hormone - metabolism; Dexamethasone - pharmacology; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - physiology; Female; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - metabolism; Histones - metabolism; Humans; Middle Aged; NF-kappa B p52 Subunit - metabolism; Placenta - metabolism; Pregnancy - metabolism; Transcription Factor RelB - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.aaa9806

Corticotropin-releasing hormone (CRH) produced in the placenta may be part of a clock that regulates the length of human gestation. Maternal plasma CRH abundance exponentially increases as pregnancy advances. Glucocorticoid stimulates CRH expression in full-term human placenta by promoting noncanonical (RelB/p52 heterodimer-mediated) nuclear factor κB (NF-κB) pathway activity. Using dexamethasone to mimic glucocorticoid exposure, we found that an epigenetic switch mediated the glucocorticoid-induced expression of CRH as gestation advances. The amount of acetylated histone H3 lysine 9 (H3K9) associated with the CRH promoter was greater in cytotrophoblasts from full-term placenta than in those from midterm placenta. Knocking down the lysine acetyltransferase CBP reduced H3K9 histone acetylation and prevented dexamethasone-induced CRH expression. Unexpectedly, knocking down the histone deacetylase HDAC1 or pharmacologically inhibiting type I and II HDACs also decreased the expression of CRH yet increased the acetylation of H3K9 and other histone regions. Both CBP and HDAC1 bound at the CRH promoter in a complex with the RelB/p52 heterodimer in a mutually dependent manner; knocking down any one factor in the complex prevented binding of the others as well as the dexamethasone-induced CRH expression. Our results suggest that glucocorticoids induce a transcription complex consisting of RelB/p52, CBP, and HDAC1 that triggers a dynamic acetylation-mediated epigenetic change to induce CRH expression in full-term human placenta.