Abstract
Background:
Lysine 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 findings:
Here, 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/significance:
Results 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Cell Line
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Female
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Histones / genetics*
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Lysine / genetics
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Lysine / metabolism
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Placenta / drug effects
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Placenta / metabolism*
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Pregnancy
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Pregnancy-Specific beta 1-Glycoproteins / genetics*
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Pregnancy-Specific beta 1-Glycoproteins / metabolism
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Promoter Regions, Genetic / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Sp1 Transcription Factor / genetics
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Sp1 Transcription Factor / metabolism
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Transcriptional Activation
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Up-Regulation / drug effects
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Up-Regulation / physiology*
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p300-CBP Transcription Factors / genetics
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p300-CBP Transcription Factors / metabolism
Substances
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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KLF6 protein, human
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors
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Pregnancy-Specific beta 1-Glycoproteins
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Proto-Oncogene Proteins
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Sp1 Transcription Factor
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trichostatin A
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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Histone Deacetylases
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Lysine
Grants and funding
This work was supported by the Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina (CONICET), the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), the Ministerio de Ciencia y Tecnología de la Provincia de Córdoba, and the Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC). S.G.-R. and G.M.P.-D. are Career Investigators of CONICET. S.A.C. was a holder of FONCYT and CONICET fellowships. A.C.R. and M.E.R. thank CONICET for their fellowships. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.