Epigenetic modulation of the protein kinase A RIIalpha (PRKAR2A) gene by histone deacetylase 1 & 2 in human smooth muscle cells

  1. Lookup NU author(s)
  2. Dr Magdalena Karolczak-Bayatti
  3. Andrew Loughney
  4. Professor Stephen Robson
  5. Professor Nick Europe-Finner
Author(s)Karolczak-Bayatti M, Loughney AD, Robson SC, Europe-Finner GN
Publication type Article
JournalJournal of Cellular and Molecular Medicine
Year2011
Volume15
Issue1
Pages94-108
ISSN (print)1582-1838
ISSN (electronic)1582-4934
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Recently we reported that the expression of the PKA regulatory subunit RIIα is dynamically regulated in human smooth muscle cells of the uterus. We showed that expression levels of mRNA/protein were substantially increased during pregnancy and decreased upon labour, changes that were mirrored by particulate type II PKA activity. This implied an important role for RIIα in maintaining uterine quiescence during pregnancy. Consequently the purpose of the present study was to identify potential mechanisms by which expression of the RIIα gene was regulated in this tissue. We indicate here that the three SpI-III (GC) binding domains within the proximal promoter region of the human RIIα gene may play important roles in modulating expression of the gene in human myometrial cells. We show that all three GC binding domains are involved in binding Sp1, Sp3, HDACs 1/2 and RbAp48 transcriptional complexes. The functional significance of these binding domains was further analysed employing in vitro luciferase reporter assays with full-length/truncated RIIα promoter constructs. Importantly we show that treatment of primary human myometrial cell cultures with the general class I/II HDAC inhibitor Trichostatin A results in an increase in mRNA/protein levels. Moreover the increase in mRNA levels appeared to be preceded by an increase in aH3, PolIIa, Sp3 and HDAC 2 binding to the three SpI-III (GC) binding sites within the RIIα promoter. These results enable us to provide a model whereby RIIα expression is epigenetically regulated in human myometrial smooth muscle cells by histone deacetylase(s) activity within the GC rich proximal promoter region of the gene.
PublisherWiley-Blackwell Publishing Ltd
URLhttp://dx.doi.org/10.1111/j.1582-4934.2009.00927.x
DOI10.1111/j.1582-4934.2009.00927.x
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