Research ArticlePhysiology

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

See allHide authors and affiliations

Science Signaling  25 Aug 2015:
Vol. 8, Issue 391, pp. ra85
DOI: 10.1126/scisignal.aaa9806

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Epigenetics in stress and labor

Pregnancy and labor are regulated by fluctuating hormone levels. Glucocorticoids stimulate production of the stress-responsive corticotropin-releasing hormone (CRH) in the placenta as the fetus nears full term. Using cultured primary trophoblasts isolated from midtrimester and full-term placenta, Di Stefano et al. found that glucocorticoids promote the expression of CRH by stimulating dynamic histone acetylation mediated by the binding of a complex containing the transcription factor nuclear factor κB (NF-κB), a histone lysine acetyltransferase, and a histone deacetylase to the CRH promoter. The findings reveal an epigenetic mechanism regulating the duration of pregnancy.


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.

View Full Text

Stay Connected to Science Signaling