Abstract
BackgroundLysine acetylation is an important post-translational modification that plays a central role in eukaryotic transcriptional activation by modifying chromatin and transcription-related factors. Human pregnancy-specific glycoproteins (PSG) are the major secreted placental proteins expressed by the syncytiotrophoblast at the end of pregnancy and represent early markers of cytotrophoblast differentiation. Low PSG levels are associated with complicated pregnancies, thus highlighting the importance of studying the mechanisms that control their expression. Despite several transcription factors having been implicated as key regulators of PSG gene family expression; the role of protein acetylation has not been explored.Methodology/Principal FindingsHere, we explored the role of acetylation on PSG gene expression in the human placental-derived JEG-3 cell line. Pharmacological inhibition of histone deacetylases (HDACs) up-regulated PSG protein and mRNA expression levels, and augmented the amount of acetylated histone H3 associated with PSG 5′regulatory regions. Moreover, PSG5 promoter activation mediated by Sp1 and KLF6, via the core promoter element motif (CPE, −147/−140), was markedly enhanced in the presence of the HDAC inhibitor trichostatin A (TSA). This effect correlated with an increase in Sp1 acetylation and KLF6 nuclear localization as revealed by immunoprecipitation and subcellular fractionation assays. The co-activators PCAF, p300, and CBP enhanced Sp1-dependent PSG5 promoter activation through their histone acetylase (HAT) function. Instead, p300 and CBP acetyltransferase domain was dispensable for sustaining co-activation of PSG5 promoter by KLF6.Conclusions/SignificanceResults are consistent with a regulatory role of lysine acetylation on PSG expression through a relaxed chromatin state and an increase in the transcriptional activity of Sp1 and KLF6 following an augmented Sp1 acetylation and KLF6 nuclear localization.
Highlights
Histone post-translational modifications have been shown to be crucial for programmed gene expression during several events of development in eukaryotes, including placental development and functioning [1]
In this report we present the first evidence that pregnancy-specific glycoproteins (PSG) gene expression can be regulated by lysine acetylation involving histone and nonhistone target proteins
We found that PSG transcripts and proteins increase after treatment of placental JEG-3 cells with histone deacetylases (HDACs) inhibitors
Summary
Histone post-translational modifications have been shown to be crucial for programmed gene expression during several events of development in eukaryotes, including placental development and functioning [1]. Histone tail acetylation has been strongly correlated with transcriptional activation [3] This reversible modification is carried out by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) [4]. They act as transcriptional co-activators with the capability to interact with a wide range of transcription factors and integrate signals from different pathways, modify histones, and remodel chromatin. Dynamic acetylation of histone and nonhistone proteins can be selectively modulated by HDAC inhibitors (HDACis), thereby regulating gene transcription by affecting chromatin assembly and/or modifying protein–protein interactions, protein stability, DNAbinding capability, transcriptional activity, and/or nuclear localization of specific protein factors [7]. Lysine acetylation is an important post-translational modification that plays a central role in eukaryotic transcriptional activation by modifying chromatin and transcription-related factors. Despite several transcription factors having been implicated as key regulators of PSG gene family expression; the role of protein acetylation has not been explored
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