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.

miR‑203 contributes to pre‑eclampsia via inhibition of VEGFA expression

“…Quantitative real-time PCR kits were purchased from Takara Biotechnology Co., Ltd. (Dalian, China). Details of the RNA extraction, cDNA conversion and RT-qPCR assays have been described previously ( 23 ). To detect the mRNA expression levels of miR-203 and VEGFA, RT-qPCR was performed in 96-well reaction plates with a total volume of 10 µl, containing the following: 1 µl cDNA template, 0.2 µl each primer, 3.6 µl diethyl pyrocarbonate-H 2 O and 5 µl SYBR-Green dye using the ABI Step One Plus™ Real-Time PCR System (Applied Biosystems; Thermo Fisher Scientific, Inc.).…”

Phosphorylation of STAT3 at Tyr705 regulates MMP-9 production in epithelial ovarian cancer

“…In this study, we showed that p-STAT3 directly interacts with a GAS element in MMP-9 gene promoter to drive gene expression of MMP-9. Given a recent study showing that STAT3 can bridge RelB/p52 heterodimers and chromatin remodeling complex like histone acetylases, we speculate that p-STAT3 may also play a cooperative role in positive regulation of MMP-9 by assisting in recruitment of RelB/p52-containing transcriptional activator complex, as observed in placental cells [ 19 , 30 ]. In other words, p-STAT3 could play multiple roles in regulation of MMPs in ovarian cancer cells.…”

Extracellular vesicles in normal pregnancy and pregnancy‐related diseases

“…Altogether, their data imply that foetal cell exosomes may contribute to the timing of birth by increasing uterine cell inflammation. Ithier et al suggest that foetal lung‐derived C4BPA plays a role in birth timing determination by utilizing proteomics analysis of exosomes from foetal cord arterial blood. They reveal that C4BPA could bind to CD40 of placental villous trophoblast to promote p100 processing to p52.…”