Research Paper Volume 12, Issue 9 pp 8434—8458
Genetic regulatory subnetworks and key regulating genes in rat hippocampus perturbed by prenatal malnutrition: implications for major brain disorders
- 1 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
- 2 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- 3 Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
- 4 International Peace Maternity and Child Health Hospital of China Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
- 5 Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
- 6 School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
- 7 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo 315000, China
- 8 Translational Medical Center for Development and Disease, Institute of Pediatrics, Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China
- 9 Department of Developmental and Behavioral Pediatrics, Pediatric Translational Medicine Institute, Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- 10 Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
received: October 5, 2019 ; accepted: April 16, 2020 ; published: May 11, 2020 ;https://doi.org/10.18632/aging.103150
How to Cite
Copyright © 2020 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objective: Many population studies have shown that maternal prenatal nutrition deficiency may increase the risk of neurodevelopmental disorders in their offspring, but its potential transcriptomic effects on brain development are not clear. We aimed to investigate the transcriptional regulatory interactions between genes in particular pathways responding to the prenatal nutritional deficiency and to explore their effects on neurodevelopment and related disorders.
Results: We identified three modules in rat hippocampus responding to maternal prenatal nutritional deficiency and found 15 key genes (Hmgn1, Ssbp1, LOC684988, Rpl23, Gga1, Rhobtb2, Dhcr24, Atg9a, Dlgap3, Grm5, Scn2b, Furin, Sh3kbp1, Ubqln1, and Unc13a) related to the rat hippocampus developmental dysregulation, of which Hmgn1, Rhobtb2 and Unc13a related to autism, and Dlgap3, Grm5, Furin and Ubqln1 are related to Alzheimer’s disease, and schizophrenia. Transcriptional alterations of the hub genes were confirmed except for Atg9a. Additionally, through modeling miRNA–mRNA-transcription factor interactions for the hub genes, we confirmed a transcription factor, Cebpa, is essential to regulate the expression of Rhobtb2. We did not find singificent singals in the prefrontal cortex responding to maternal prenatal nutritional deficiency.
Conclusion: These findings demonstrated that these genes with the three modules in rat hippocampus involved in synaptic development, neuronal projection, cognitive function, and learning function are significantly enriched hippocampal CA1 pyramidal neurons and suggest that three genetic regulatory subnetworks and thirteen key regulating genes in rat hippocampus perturbed by a prenatal nutrition deficiency. These genes and related subnetworks may be prenatally involved in the etiologies of major brain disorders, including Alzheimer’s disease, autism, and schizophrenia.
Methods: We compared the transcriptomic differences in the hippocampus and prefrontal cortex between 10 rats with prenatal nutritional deficiency and 10 rats with prenatal normal chow feeding by differential analysis and co-expression network analysis. A network-driven integrative analysis with microRNAs and transcription factors was performed to define significant modules and hub genes responding to prenatal nutritional deficiency. Meanwhile, the module preservation test was conducted between the hippocampus and prefrontal cortex. Expression levels of the hub genes were further validated with a quantitative real-time polymerase chain reaction based on additional 40 pairs of rats.