title: Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: N G
authors.initials: NG
authors.lastname: Than
authors.affiliation: 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.
authors.forename: R
authors.initials: R
authors.lastname: Romero
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Erez
authors.affiliation: 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.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Bhatti
authors.affiliation: Zymo Research Corporation, Irvine, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Leavitt
authors.affiliation: Zymo Research Corporation, Irvine, CA, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: El-Azzamy
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: LaJeunesse
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Balogh
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Szalai
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Land
authors.affiliation: 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.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: S S
authors.initials: SS
authors.lastname: Hassan
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Chaiworapongsa
authors.affiliation: Zymo Research Corporation, Irvine, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Krispin
authors.affiliation: 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.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: A L
authors.initials: AL
authors.lastname: Tarca
authors.affiliation: Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Papp
authors.affiliation: Behringwerke AG, Marburg/Lahn, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bohn
mesh_terms: D020121:5' Untranslated Regions; D002454:Cell Differentiation; D002888:Chromosomes, Human, Pair 19; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D005260:Female; D037161:Galectins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D005810:Multigene Family; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D014157:Transcription Factors / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D037161:Galectins; D014157:Transcription Factors
keywords: ALU; AP2; Anthropoid primate; ESRRG; Epigenome; GATA; GCM1; LINE; Lectin; PP13; Pregnancy; Syncytiotrophoblast; TEF5