Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia

Jiawei Xu; Guang He; Jingde Zhu; Xinyao Zhou; David St Clair; Teng Wang; Yuqian Xiang; Qingzhu Zhao; Qinghe Xing; Yun Liu; Lei Wang; Qiaoli Li; Lin He; Xinzhi Zhao

doi:10.1093/ijnp/pyu054

Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia

Jiawei Xu, Guang He, Jingde Zhu, Xinyao Zhou, David St Clair, Teng Wang, Yuqian Xiang, Qingzhu Zhao, Qinghe Xing, Yun Liu, Lei Wang, Qiaoli Li, Lin He, Xinzhi Zhao

Applied Medicine

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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.

Original language	English
Article number	pyu054
Journal	International Journal of Neuropsychopharmacology
Volume	18
Issue number	4
Early online date	24 Jan 2015
DOIs	https://doi.org/10.1093/ijnp/pyu054
Publication status	Published - Feb 2015

Bibliographical note

This work was supported by the 973 Program (2009825606 to Xinzhi Zhao, 2010CB529600 to Guang He), the National Natural Science Foundation of China (30800616 to Xinzhi Zhao, 31171237 to Guang He, 81121001 to Lei Wang), the National Key Technology R&D Program (2012BAI01B09 to Lin He), the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601 to Lin He), the Shanghai Rising-Star Program (09QA1400500 to Xinzhi Zhao) and the Shanghai Leading Academic Discipline Project (B205). Drs Xu and G He designed and conducted the experiments and collected data. Dr J.ZH. also analyzed data and prepared the first draft of the manuscript. Dr Zhu designed and supervised experiments involving MBD sequencing. Drs T. Wang, Xiang, and Xinyao Zhou provided help in performing experiments and contributed to discussions. Drs Xing and St Clair helped in data analyses and in writing the manuscript. Dr Liu provided technical help in next-generation sequencing. Dr L Wang provided technical help in DNA methylation validation using MassARRAY platform. Dr Li provided reagents and technical advice. Dr Lin He supervised the project and edited the manuscript. Dr Guang He designed the experiments and edited the manuscript. Dr Xinzhi Zhao designed and supervised experiments analyzed data and wrote the manuscript. This work was supported by grants to Drs Lin He Guang He, and Xinzhi Zhao.

Keywords

DNA methylation
Hippocampus
Prefrontal cortex
Schizophrenia
Transcriptome

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Xu, J., He, G., Zhu, J., Zhou, X., Clair, D. S., Wang, T., Xiang, Y., Zhao, Q., Xing, Q., Liu, Y., Wang, L., Li, Q., He, L., & Zhao, X. (2015). Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia. International Journal of Neuropsychopharmacology, 18(4), Article pyu054. https://doi.org/10.1093/ijnp/pyu054

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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.",

keywords = "DNA methylation, Hippocampus, Prefrontal cortex, Schizophrenia, Transcriptome",

author = "Jiawei Xu and Guang He and Jingde Zhu and Xinyao Zhou and Clair, {David St} and Teng Wang and Yuqian Xiang and Qingzhu Zhao and Qinghe Xing and Yun Liu and Lei Wang and Qiaoli Li and Lin He and Xinzhi Zhao",

note = "This work was supported by the 973 Program (2009825606 to Xinzhi Zhao, 2010CB529600 to Guang He), the National Natural Science Foundation of China (30800616 to Xinzhi Zhao, 31171237 to Guang He, 81121001 to Lei Wang), the National Key Technology R&D Program (2012BAI01B09 to Lin He), the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601 to Lin He), the Shanghai Rising-Star Program (09QA1400500 to Xinzhi Zhao) and the Shanghai Leading Academic Discipline Project (B205). Drs Xu and G He designed and conducted the experiments and collected data. Dr J.ZH. also analyzed data and prepared the first draft of the manuscript. Dr Zhu designed and supervised experiments involving MBD sequencing. Drs T. Wang, Xiang, and Xinyao Zhou provided help in performing experiments and contributed to discussions. Drs Xing and St Clair helped in data analyses and in writing the manuscript. Dr Liu provided technical help in next-generation sequencing. Dr L Wang provided technical help in DNA methylation validation using MassARRAY platform. Dr Li provided reagents and technical advice. Dr Lin He supervised the project and edited the manuscript. Dr Guang He designed the experiments and edited the manuscript. Dr Xinzhi Zhao designed and supervised experiments analyzed data and wrote the manuscript. This work was supported by grants to Drs Lin He Guang He, and Xinzhi Zhao.",

year = "2015",

month = feb,

doi = "10.1093/ijnp/pyu054",

language = "English",

volume = "18",

journal = "International Journal of Neuropsychopharmacology",

issn = "1461-1457",

publisher = "Cambridge University Press",

number = "4",

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TY - JOUR

T1 - Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains

T2 - Implications for Schizophrenia

AU - Xu, Jiawei

AU - He, Guang

AU - Zhu, Jingde

AU - Zhou, Xinyao

AU - Clair, David St

AU - Wang, Teng

AU - Xiang, Yuqian

AU - Zhao, Qingzhu

AU - Xing, Qinghe

AU - Liu, Yun

AU - Wang, Lei

AU - Li, Qiaoli

AU - He, Lin

AU - Zhao, Xinzhi

N1 - This work was supported by the 973 Program (2009825606 to Xinzhi Zhao, 2010CB529600 to Guang He), the National Natural Science Foundation of China (30800616 to Xinzhi Zhao, 31171237 to Guang He, 81121001 to Lei Wang), the National Key Technology R&D Program (2012BAI01B09 to Lin He), the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601 to Lin He), the Shanghai Rising-Star Program (09QA1400500 to Xinzhi Zhao) and the Shanghai Leading Academic Discipline Project (B205). Drs Xu and G He designed and conducted the experiments and collected data. Dr J.ZH. also analyzed data and prepared the first draft of the manuscript. Dr Zhu designed and supervised experiments involving MBD sequencing. Drs T. Wang, Xiang, and Xinyao Zhou provided help in performing experiments and contributed to discussions. Drs Xing and St Clair helped in data analyses and in writing the manuscript. Dr Liu provided technical help in next-generation sequencing. Dr L Wang provided technical help in DNA methylation validation using MassARRAY platform. Dr Li provided reagents and technical advice. Dr Lin He supervised the project and edited the manuscript. Dr Guang He designed the experiments and edited the manuscript. Dr Xinzhi Zhao designed and supervised experiments analyzed data and wrote the manuscript. This work was supported by grants to Drs Lin He Guang He, and Xinzhi Zhao.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - DNA methylation

KW - Hippocampus

KW - Prefrontal cortex

KW - Schizophrenia

KW - Transcriptome

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U2 - 10.1093/ijnp/pyu054

DO - 10.1093/ijnp/pyu054

M3 - Article

AN - SCOPUS:84929611668

SN - 1461-1457

VL - 18

JO - International Journal of Neuropsychopharmacology

JF - International Journal of Neuropsychopharmacology

IS - 4

M1 - pyu054

ER -

Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia

Abstract

Bibliographical note

Keywords

UN SDGs

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