Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex
Open accessAbstract
BACKGROUND: MicroRNAs are small RNA molecules that regulate the translation of protein from gene transcripts and are a powerful mechanism to regulate gene networks. Next-generation sequencing technologies have produced important insights into gene transcription changes that occur in the brain of individuals diagnosed with autism spectrum disorder (asd). However, these technologies have not yet been employed to uncover changes in microRNAs in the brain of individuals diagnosed with asd. METHODS: Small RNA next-generation sequencing was performed on RNA extracted from 12 human autism brain samples and 12 controls. Real-time PCR was used to validate a sample of the differentially expressed microRNAs, and bioinformatic analysis determined common pathways of gene targets. MicroRNA expression data was correlated to genome-wide DNA methylation data to determine if there is epigenetic regulation of dysregulated microRNAs in the autism brain. Luciferase assays, real-time PCR, and Western blot analysis were used to determine how dysregulated microRNAs may regulate the expression and translation of an autism-related gene transcript. RESULTS: We determined that miR-142-5p, miR-142-3p, miR-451a, miR-144-3p, and miR-21-5p are overexpressed in the asd brain. Furthermore, the promoter region of the miR-142 gene is hypomethylated in the same brain samples, suggesting that epigenetics plays a role in dysregulation of microRNAs in the brain. Bioinformatic analysis revealed that these microRNAs target genes that are involved in synaptic function. Further bioinformatic analysis, coupled with in vitro luciferase assays, determined that miR-451a and miR-21-5p can target the oxytocin receptor (OXTR) gene. OXTR gene expression is increased in these same brain samples, and there is a positive correlation between miR-21-5p and OXTR expression. However, miR-21-5p expression negatively correlates to production of OXTR protein from the OXTR transcript. Therefore, we suggest that miR-21-5p may attenuate OXTR expression in the human autism brain. CONCLUSIONS: Our data suggests that dysregulation of microRNAs may play a biological role in the brain of individuals of autism. In addition, we suggest an interaction between epigenetic mechanisms and microRNA dysregulation in the brain. Overall, this data adds an important link in our understanding of the molecular events that are dysregulated in the brain of individuals diagnosed with autism.
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Both prior studies examined only a single cortical region of interest, rather than multiple neighboring and distant areas as the current study did.
“In addition, both studies examined only a single cortical region of interest, rather than multiple neighboring and distant areas as we did in the current study.”
From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [57]
Unlike the current study, which used histological sections to preserve neuroanatomy, both prior studies worked with tissue homogenates.
“Finally, unlike the current study, which used histological sections to preserve neuroanatomy, both of these prior studies worked with tissue homogenates.”
From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [57]
Mor et al. reported increased OXTR mRNA in the prefrontal cortex of ASD specimens.
“Gregory et al.58 reported decreased OXTR mRNA in the superior temporal gyrus of ASD specimens, but Mor et al.57 reported increased OXTR mRNA in the prefrontal cortex of ASD specimens.”
From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [57]
Prior studies focused primarily on mechanisms that regulate OXTR gene expression and did not directly measure binding to mature, cell-surface OXTR protein.
“However, these studies focused primarily on the mechanisms that regulate OXTR gene expression (microRNAs57 and epigenetics58) and did not directly measure binding to mature, cell-surface OXTR protein, as receptor autoradiography does, which was used in this study.”
From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [57]
Two studies have previously examined the levels of OXTR gene transcripts in postmortem ASD brain specimens, in the prefrontal cortex and temporal cortex.
“Two studies have previously examined the levels of OXTR gene transcripts in postmortem ASD brain specimens (in the prefrontal cortex57 and temporal cortex58).”
From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [57]
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- Authors
- Mor, M., Nardone, S., Sams, D. S., & Elliott, E.
- Affiliations
- Bar-Ilan University (IL)
- Corresponding author
- Elliott, Evan
- Venue
- Molecular Autism
- Published
- 2015-08-14
- Volume
- 6
- Issue
- 1
- Pages
- 46-46
- ISSN
- 2040-2392 (ISSN-L)
- PMC
- PMC4535255
- OpenAlex
- W1484555099
- Cited by
- 118
- References
- 45
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 8 · 2023: 14 · 2022: 11 · 2021: 14 · 2020: 12 · 2019: 12 · 2018: 8 · 2017: 13 · 2016: 8
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Autism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Bar-Ilan University
- Israel Science Foundation (1047/12)
- National Institute for Psychobiology in Israel, Hebrew University of Jerusalem
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, microRNA dysregulation, miR-142, promoter hypomethylation, DNA methylation, oxytocin receptor, miR-21-5p, miR-451a, miR-144-3p, miR-142-5p, epigenetic regulation, prefrontal cortex, synaptic function
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