title: Prenatal nutritional deficiency reprogrammed postnatal gene expression in mammal brains: implications for schizophrenia.
abstract: BACKGROUND
  Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia.
  
  
  METHODS
  The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure.
  
  
  RESULTS
  In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37×10(-9) and 5.36×10(-9), respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring.
  
  
  CONCLUSIONS
  Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia.
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Jiawei
authors.initials: J
authors.lastname: Xu
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Guang
authors.initials: G
authors.lastname: He
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Jingde
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Xinyao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Xing
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair). xzzhao@fudan.edu.cn helin@bio-x.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Afﬁliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair). xzzhao@fudan.edu.cn helin@bio-x.cn.
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D019175:DNA Methylation; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D010641:Phenotype; D017397:Prefrontal Cortex / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D039401:Prenatal Nutritional Physiological Phenomena; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia; D013217:Starvation / Q000503:physiopathology*
chemical_list: D051272:Glucose Transporter Type 1; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; C495679:Slc2a1 protein, rat
keywords: DNA methylation; hippocampus; prefrontal cortex; schizophrenia; transcriptome