Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum
Open accessAbstract
Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription factor, previously implicated in autism, is essential for normal cerebellar patterning and development. We previously reported EN-2 overexpression associated with promoter DNA hypermethylation in the autism cerebellum but because traditional DNA methylation methodology cannot distinguish 5-methylcytosine (5-mC) from 5-hmC, we now extend our investigation by quantifying global and gene-specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the autism cerebellum and accompanied by increases in the expression of de novo methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3, and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage. Within the EN-2 promoter, there was a significant positive correlation between 5-hmC content and EN-2 gene expression. Based on reports of reduced MeCP2 affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a significant decrease in repressive MeCP2 binding that may contribute to the aberrant overexpression of EN-2. Because normal cerebellar development depends on perinatal EN-2 downregulation, the sustained postnatal overexpression suggests that a critical window of cerebellar development may have been missed in some individuals with autism with downstream developmental consequences. Epigenetic regulation of the programmed on-off switches in gene expression that occur at birth and during early brain development warrants further investigation.
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DNA hydroxymethylation has been shown to regulate gene expression in the cerebellum of patients with autism.
“DNA hydroxymethylation has also been shown to regulate gene expression in the cerebellum of patients with autism [ 92 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [92]
Findings of increased global DNA methylation and hydroxymethylation in autistic patients align with elevated DNMT expression.
“which aligns with findings of increased global DNA methylation and hydroxymethylation in these patients [ 92 , 152 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [92]
In the cerebellum of autistic patients, DNMT1, 3A, and 3B expression are elevated compared with neurotypical controls.
“In the cerebellum of autistic patients, DNMT1, 3A, and 3B expression are elevated compared with neurotypical controls [ 92 , 152 ], which aligns with findings of increased global DNA methylation and hydroxymethylation in these patients [ 92 , 152 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [92]
Independent of specific genetic mutations, changes in global DNA methylation and DNMT expression have also been observed in patients with ASD.
“Independent of specific genetic mutations, changes in global DNA methylation and DNMT expression have also been observed in patients with ASD.”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [92]
Follow-up studies confirmed elevated EN2 DNA hydroxymethylation in ASD cerebellum relative to controls.
“Although seemingly counterintuitive, follow-up studies to distinguish DNA methylation from hydroxymethylation, confirmed elevated EN2 DNA hydroxymethylation in ASD cerebellum relative to controls [ 92 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [92]
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- Authors
- James, S. J., Shpyleva, S., Melnyk, S., Pavliv, O., & Pogribny, I. P.
- Affiliations
- Arkansas Children's Hospital (US)
- National Center for Toxicological Research (US)
- Corresponding author
- James, S J
- Venue
- Translational Psychiatry
- Published
- 2014-10-07
- Volume
- 4
- Issue
- 10
- Pages
- e460-e460
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC4350522
- OpenAlex
- W2092559397
- Cited by
- 79
- References
- 55
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 12 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 2
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Arkansas Biosciences Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD051873)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- 5-hydroxymethylcytosine, Engrailed-2, autism spectrum disorder, cerebellum, DNA methylation, DNMT3A, DNMT3B, TET1, TET3, oxidative DNA damage, homeodomain transcription factor, cerebellar development, gene expression regulation, epigenetic regulation
- MeSH terms
- Engrailed 2 Protein, Adolescent, Autistic Disorder, Cerebellum, Cytosine, Female, Humans, Male, Nerve Tissue Proteins, Promoter Regions, Genetic, Gene Expression, Homeodomain Proteins, 5-Methylcytosine, Methyl-CpG-Binding Protein 2
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