Conserved role of intragenic DNA methylation in regulating alternative promoters
Open accessAbstract
Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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DNA methylation is associated with both increased and decreased gene expression and other genomic functions including alternative splicing and promoter usage.
“DNA methylation is actually associated with both increased and decreased gene expression (Wagner et al., 2014) and other genomic functions including alternative splicing and promoter usage (Maunakea et al., 2010)”
From DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia (2021) · cites this paper as Maunakea et al., 2010
The paper reports that tissue-specific DNA methylation regulates intragenic promoter activity and alternative transcripts (Abstract; page not provided), supporting the promoter-usage part attributed to Maunakea et al. Our copy does not establish an association with alternative splicing; a search for “splicing” found no relevant passage. The increased-and-decreased-expression clause is cited to Wagner et al., not to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlternative promoters have dynamic intragenic DNA methylation across human tissues.
“Alternative promoters have dynamic intragenic DNA methylation across human tissues20”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [20]
The SHANK3 analysis (section labeled Abstract; page unavailable) reports that intragenic alternative promoters have tissue-specific DNA methylation and that their methylation and expression patterns are similar in matched human and mouse tissues. The paper supports variation across human tissues at this locus, but its broader tissue comparisons rely substantially on mouse data; it does not establish the claim generally for alternative promoters across human tissues. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGene bodies have high levels of DNA methylation across both MP and SP genes.
“Gene bodies have high levels of DNA methylation20,53, which we observed across both MP and SP genes”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [20]
There are additional start sites in the human and mouse SHANK3 gene that may lead to shorter products truncated at the N terminus (termed 22t and 32t).
“A recent report has indicated that there are additional start sites in the human and mouse SHANK3 gene that may lead to shorter products, truncated at the N terminus (termed 22t and 32t in that report [51]).”
From Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication (2010) · cites this paper as [51]
Expression of Shank3 isoforms is cell type-specific and developmentally regulated.
“The expression of Shank3 isoforms is cell type-specific and developmentally regulated (Lim et al., 1999; Maunakea et al., 2010).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Maunakea et al., 2010
SHANK genes have complex transcriptional regulation with multiple intragenic promoters and extensive alternatively spliced exons in both humans and mice.
“SHANK genes display a complex transcriptional regulation with multiple intragenic promoters and extensive alternatively spliced exons both in humans and mice (Leblond et al., 2012; Lim et al., 1999; Maunakea et al., 2010; McWilliams et al., 2004; Redecker et al., 2006; Wang et al., 2011; Wilson et al., 2003).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Maunakea et al., 2010
DNA methylation and histone deacetylase inhibitors modulate isoform-specific Shank3 expression in cultured neurons.
“Both DNA methylation and histone deacetylase inhibitors have been shown to modulate the isoform specific gene expression of Shank3 in cultured neurons (Beri et al., 2007; Maunakea et al., 2010).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Maunakea et al., 2010
SHANK3 has five CpG islands across the gene, and these islands display brain-specific and cell type-specific DNA methylation.
“To add further complexity, SHANK3 has five CpG islands across the gene and these CpG islands display brain-specific and cell type-specific DNA methylation (Figure 1A) (Beri et al., 2007; Ching et al., 2005; Maunakea et al., 2010).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Maunakea et al., 2010
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- Authors
- Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D’Souza, C., Fouse, S. D., Johnson, B. E., Hong, C., Nielsen, C., Zhao, Y., Turecki, G., Delaney, A., Varhol, R., Thiessen, N., Shchors, K., Heine, V. M., Rowitch, D. H., Xing, X., Fiore, C., Schillebeeckx, M., Jones, S. J. M., Haussler, D., Marra, M. A., Hirst, M., Wang, T., & Costello, J. F.
- Affiliations
- University of California, San Francisco (US)
- BC Cancer Agency (CA)
- University of California, Santa Cruz (US)
- Douglas Mental Health University Institute (CA)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wang, Ting
- Costello, Joseph F.
- ORCID
- Venue
- Nature
- Published
- 2010-07
- Volume
- 466
- Issue
- 7303
- Pages
- 253-257
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3998662
- OpenAlex
- W2065498897
- Cited by
- 1,743
- References
- 30
- Citations by year
- 2026: 46 · 2025: 58 · 2024: 55 · 2023: 65 · 2022: 85 · 2021: 131 · 2020: 119 · 2019: 92 · 2018: 122 · 2017: 118 · 2016: 110 · 2015: 161 · 2014: 165 · 2013: 158 · 2012: 147
- FWCI
- 53.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- GlaxoSmithKline
- Genome Canada
- Genome British Columbia
- National Institutes of Health
- National Institute of Environmental Health Sciences (U01ES017154)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- alternative promoters, gene body methylation, CpG islands, human brain, histone H3 lysine 4 trimethylation, histone modifications, tissue-specific gene expression, transcription initiation, gene expression regulation, epigenetics, human-mouse comparison, transcription elongation
- MeSH terms
- Animals, Brain, Carrier Proteins, Cell Line, Frontal Lobe, Gene Expression Regulation, Histones, Humans, Male, Mice, Inbred C57BL, Microfilament Proteins, Middle Aged, Nerve Tissue Proteins, Organ Specificity, Promoter Regions, Genetic, Transcription, Genetic, Conserved Sequence, CpG Islands, DNA Methylation, DNA, Intergenic, Mice
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