Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia

N G Than; R Romero; Y Xu; O Erez; Z Xu; G Bhatti; R Leavitt; T H Chung; H El-Azzamy; C LaJeunesse; B Wang; A Balogh; G Szalai; S Land; Z Dong; S S Hassan; T Chaiworapongsa; M Krispin; C J Kim; A L Tarca; Z Papp; H Bohn

doi:10.1016/j.placenta.2014.07.015

Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia

Placenta. 2014 Nov;35(11):855-65. doi: 10.1016/j.placenta.2014.07.015. Epub 2014 Aug 26.

Authors

N G Than¹, R Romero², Y Xu³, O Erez⁴, Z Xu³, G Bhatti³, R Leavitt⁵, T H Chung⁵, H El-Azzamy³, C LaJeunesse³, B Wang³, A Balogh⁶, G Szalai³, S Land⁷, Z Dong³, S S Hassan⁸, T Chaiworapongsa⁸, M Krispin⁵, C J Kim⁹, A L Tarca¹⁰, Z Papp¹¹, H Bohn¹²

Affiliations

¹ Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: nthan@med.wayne.edu.
² Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA. Electronic address: romeror@mail.nih.gov.
³ Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA.
⁴ Department of Obstetrics and Gynecology, Ben-Gurion University, Beer-Sheva, Israel.
⁵ Zymo Research Corporation, Irvine, CA, USA.
⁶ Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA; Department of Immunology, Eotvos Lorand University, Budapest, Hungary.
⁷ Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
⁸ Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
⁹ Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.
¹⁰ Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
¹¹ Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary.
¹² Behringwerke AG, Marburg/Lahn, Germany.

Abstract

Introduction: The dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus.

Materials and methods: This study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation.

Results and discussion: The villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5' untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA.

Conclusions: These findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface.

Keywords: ALU; AP2; Anthropoid primate; ESRRG; Epigenome; GATA; GCM1; LINE; Lectin; PP13; Pregnancy; Syncytiotrophoblast; TEF5.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

5' Untranslated Regions
Cell Differentiation
Chromosomes, Human, Pair 19*
Down-Regulation
Epigenesis, Genetic
Evolution, Molecular*
Female
Galectins / genetics*
Galectins / metabolism
Humans
Multigene Family
Pre-Eclampsia / metabolism*
Pregnancy
Transcription Factors / metabolism
Trophoblasts / cytology
Trophoblasts / metabolism*

Substances

5' Untranslated Regions
Galectins
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding