Epigenetic Gene-Regulatory Loci in Alu Elements Associated with Autism Susceptibility in the Prefrontal Cortex of ASD-Reference-Cited by-同舟云学术

Epigenetic Gene-Regulatory Loci in Alu Elements Associated with Autism Susceptibility in the Prefrontal Cortex of ASD

Published:2023-04-19 Issue:8 Volume:24 Page:7518
ISSN:1422-0067
Container-title:International Journal of Molecular Sciences
language:en
Short-container-title:IJMS

Author:

Saeliw Thanit¹,Kanlayaprasit Songphon²,Thongkorn Surangrat¹³,Songsritaya Kwanjira⁴,Sanannam Bumpenporn⁵,Sae-Lee Chanachai⁶⁷,Jindatip Depicha²⁸^ORCID,Hu Valerie W.⁹^ORCID,Sarachana Tewarit²^ORCID

Affiliation:

1. The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand

2. Systems Neuroscience of Autism and Psychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand

3. Department of Biotechnology and Biomedicine (DTU Bioengineering), Technical University of Denmark, 2800 Kongens Lyngby, Denmark

4. The M.Sc. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand

5. Division of Anatomy, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand

6. Research Division, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

7. Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

8. Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand

9. Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA

Abstract

Alu elements are transposable elements that can influence gene regulation through several mechanisms; nevertheless, it remains unclear whether dysregulation of Alu elements contributes to the neuropathology of autism spectrum disorder (ASD). In this study, we characterized transposable element expression profiles and their sequence characteristics in the prefrontal cortex tissues of ASD and unaffected individuals using RNA-sequencing data. Our results showed that most of the differentially expressed transposable elements belong to the Alu family, with 659 loci of Alu elements corresponding to 456 differentially expressed genes in the prefrontal cortex of ASD individuals. We predicted cis- and trans-regulation of Alu elements to host/distant genes by conducting correlation analyses. The expression level of Alu elements correlated significantly with 133 host genes (cis-regulation, adjusted p < 0.05) associated with ASD as well as the cell survival and cell death of neuronal cells. Transcription factor binding sites in the promoter regions of differentially expressed Alu elements are conserved and associated with autism candidate genes, including RORA. COBRA analyses of postmortem brain tissues showed significant hypomethylation in global methylation analyses of Alu elements in ASD subphenotypes as well as DNA methylation of Alu elements located near the RNF-135 gene (p < 0.05). In addition, we found that neuronal cell density, which was significantly increased (p = 0.042), correlated with the expression of genes associated with Alu elements in the prefrontal cortex of ASD. Finally, we determined a relationship between these findings and the ASD severity (i.e., ADI-R scores) of individuals with ASD. Our findings provide a better understanding of the impact of Alu elements on gene regulation and molecular neuropathology in the brain tissues of ASD individuals, which deserves further investigation.

Funder

Program Management Unit for Human Resources and Institutional Development, Research and Innovation

Ratchadapisek Somphot Fund for Supporting Research Unit, Chulalongkorn University

Thailand Science research and Innovation Fund Chulalongkorn University

Second Century Fund (C2F), Chulalongkorn University

90th Anniversary Chulalongkorn University Fund Ratchadaphiseksomphot Endowment Fund, Graduate School, Chulalongkorn University

National Research Council of Thailand

The Scholarship from the Graduate School, Chulalongkorn University to commemorate the 72nd anniversary of his Majesty King Bhumibol Aduladej

Royal Golden Jubilee Ph.D. Program Scholarship from the Thailand Research Fund and National Research Council of Thailand

90th Anniversary Chulalongkorn University Fund

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Link

https://www.mdpi.com/1422-0067/24/8/7518/pdf

Reference87 articles.

1. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5®), American Psychiatric Pub.

2. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020;Maenner;MMWR Surveill. Summ.,2023

3. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders;Schaefer;Genet. Med.,2008

4. The contribution of environmental exposure to the etiology of autism spectrum disorder;Bolte;Cell. Mol. Life Sci.,2019

5. Kanlayaprasit, S., Thongkorn, S., Panjabud, P., Jindatip, D., Hu, V.W., Kikkawa, T., Osumi, N., and Sarachana, T. (2021). Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex. Int. J. Mol. Sci., 22.