title: RelB/p52-mediated NF-κB signaling alters histone acetylation to increase the abundance of corticotropin-releasing hormone in human placenta.
abstract: 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.
authors: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
authors: Valeria
authors: V
authors: Di Stefano
authors: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. wangbi@rwjms.rutgers.edu rosentj@rwjms.rutgers.edu.
authors: Bingbing
authors: B
authors: Wang
authors: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
authors: Nataliya
authors: N
authors: Parobchak
authors: Department of Obstetrics, Gynecology, and Women's Health, Rutgers New Jersey Medical School, Newark, NJ 07101, USA.
authors: Natalie
authors: N
authors: Roche
authors: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. wangbi@rwjms.rutgers.edu rosentj@rwjms.rutgers.edu.
authors: Todd
authors: T
authors: Rosen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D005260:Female; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000378:metabolism*
chemical_list: D006657:Histones; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C497593:RELB protein, human; D051841:Transcription Factor RelB; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2