title: 5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human.
abstract: Preeclampsia and gestational diabetes mellitus (GDM) are the most common clinical conditions in pregnancy that could result in adverse in utero environments. Fetal exposure to poor environments may raise the long-term risk of postnatal disorders, while epigenetic modifications could be involved. Recent research has implicated involvement of 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine, via oxidation by ten-eleven translocation (TET) enzymes, in DNA methylation-related plasticity. Here, we show that the TET2 expression and 5hmC abundance are significantly altered in the umbilical veins of GDM and preeclampsia. Genome-wide profiling of 5hmC revealed its specific reduction on intragenic regions from both GDM and preeclampsia compared to healthy controls. Gene Ontology analysis using loci bearing unique GDM- and preeclampsia-specific loss-of-5hmC indicated its impact on several critical biological pathways. Interestingly, the substantial alteration of 5hmC on several transposons and repetitive elements led to their differential expression. The alteration of TET expression, 5hmC levels and 5hmC-mediated transposon activity was further confirmed using established hypoxia cell culture model, which could be rescued by vitamin C, a known activator of TET proteins. Together, these results suggest that adverse pregnancy environments could influence 5hmC-mediated epigenetic profile and contribute to abnormal development of fetal vascular systems that may lead to postnatal diseases.
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Mingxi M
authors.initials: MM
authors.lastname: Song
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Tao
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA peng.jin@emory.edu xuzhice@suda.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China peng.jin@emory.edu xuzhice@suda.edu.cn.
authors.forename: Zhice
authors.initials: Z
authors.lastname: Xu
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000328:Adult; D001205:Ascorbic Acid / Q000008:administration & dosage; D019175:DNA Methylation / Q000235:genetics*; D004251:DNA Transposable Elements / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D016640:Diabetes, Gestational / Q000235:genetics* / Q000503:physiopathology; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D011225:Pre-Eclampsia / Q000235:genetics* / Q000503:physiopathology; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D049308:Dioxygenases; C541081:TET2 protein, human; D001205:Ascorbic Acid