Differential expression of PPP1R12A transcripts, including those harbouring alternatively spliced micro-exons, in placentae from complicated pregnancies

Frew, Edward, Sainty, Rebecca, Chappell-Maor, Louise, Bone, Caitlin, Daskeviciute, Dagne, Russell, Sarah, Buhigas, Claudia, Iglesias-Platas, Isabel, Lartey, Jon and Monk, David (2024) Differential expression of PPP1R12A transcripts, including those harbouring alternatively spliced micro-exons, in placentae from complicated pregnancies. Placenta, 151. pp. 1-9. ISSN 0143-4004

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Introduction: Placenta-associated pregnancy complications, including pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are conditions postulated to originate from initial failure of placentation, leading to clinical sequelae indicative of endothelial dysfunction. Vascular smooth muscle aberrations have also been implicated in the pathogenesis of both disorders via smooth muscle contractility and relaxation mediated by Myosin Light Chain Phosphatase (MLCP) and the oppositional contractile action of Myosin Light Chain Kinase. PPP1R12A is a constituent part of the MLCP complex responsible for dephosphorylation of myosin fibrils. We hypothesize that alternative splicing of micro-exons result in isoforms lacking the functional leucine zipper (LZ) domain which may give those cells expressing these alternative transcripts a tendency towards contraction and vasoconstriction. Methods: Expression was determined by qRT-PCR. Epigenetic profiling consisted of bisulphite-based DNA methylation analysis and ChIP for underlying histone modifications. Results: We identified several novel transcripts with alternative micro-exon inclusion that would produce LZ- PPP1R12A protein. qRT-PCR revealed some isoforms, including the PPP1R12A canonical transcript, are differentially expressed in placenta biopsies from PE and IUGR samples compared to uncomplicated pregnancies. Discussion: We propose that upregulation of PPP1R12A expression in complicated pregnancies may be due to enhanced promoter activity leading to increased transcription as a response to physiological stress in the placenta, which we show is independent of promoter DNA methylation.

Item Type: Article
Additional Information: Funding information: This work was funded by the Spanish Ministry of Economy and Competitiveness (MINECO BFU2017-85571-R to DM), co-funded with the European Union Regional Development Fund (FEDER), the Medical Research Council (MR/T032863/1 to DM), the National Institute for Health and Care Research (NIHR) Capability Fund, the UKRI Biotechnology and Biological Sciences Research Council (BB/V016156/1 to DM). RS and DD received BBSRC Norwich Research Park Biosciences Doctoral Training Partnership fellowships (BB/T008717/1). The Lartey group received funding from the Academic Clinical fellowship fund of the NIHR. The human embryonic and fetal material was provided by the Joint MRC/Wellcome Trust (Grants MR/006237/1, MR/X008304/1 and 226202/Z/22/Z) to the Human Developmental Biology Resource (https://www.hdbr.org).
Uncontrolled Keywords: dna methylation,micro-exons,ppp1r12a,placenta,reproductive medicine,obstetrics and gynaecology,developmental biology ,/dk/atira/pure/subjectarea/asjc/2700/2743
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Science > Research Groups > Wheeler Group
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 19 Apr 2024 14:30
Last Modified: 14 May 2024 16:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/94981
DOI: 10.1016/j.placenta.2024.04.005


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