Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters

By A. Maunakea, R. Nagarajan, M. Bilenky, Tracy J. Ballinger, Cletus D'souza, S. Fouse, Brett E. Johnson, C. Hong, C. Nielsen, Yongjun Zhao and 16 more. Nature, 2010

1,715 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/db3294c991b47c70ba79ba9b6d18698770e45646

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Citations in the corpus

Dynamic DNA methylation across diverse human cell lines and tissues (2013, background): “Recent studies have proposed that cryptic or alternative promoters, marked by H3K4me3 and CAGE tags, may appear as promoter-like methylation in gene bodies (Illingworth et al. 2010; Maunakea et al. 2010; Deaton et al. 2011).”
Cancer epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance (2014, background): “…there is a hierarchical arrangement for such populations versus their less tumorigenic counterparts or whether there is plasticity in which such stem-cell-like populations can always be generated, especially under stress situations, from other cells in the population (Meacham and Morrison, 2013).”
DNA methylation: superior or subordinate in the epigenetic hierarchy? (2011, background): “, who regard it as more a regulator of alternative promoter usage.(51) They discovered that CGIs in gene bodies overlapped significantly with marks of transcriptional initiation and that unmethylated CGIs also overlapped with trimethylated H3K4, a histone modification enriched at promoters.”
DNA Methylation and Its Basic Function (2013, background): “…intragenic and gene body regions can have tissue-specific patterns of methylation, CpG islands associated with transcription start sites rarely show tissue-specific methylation patterns (Rakyan et al, 2004; Eckhardt et al, 2006; Meissner et al, 2008; Illingworth et al, 2010; Maunakea et al, 2010).”
Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. (2012, background): “Alternative splicing and alternative transcription start sites, as well as internal promoter regulation, result in Shank isoforms that lack another domain (Boeckers et al. 1999; Lim et al. 1999; Maunakea et al. 2010).”
Gene Body Methylation can alter Gene Expression and is a Therapeutic Target in Cancer (2014, background): “The function of gene body DNAmethylation is poorly understood, although several recent studies have begun to investigate the potential for how gene body DNA methylation affects gene expression (Kulis et al., 2012; Lister et al., 2009; Maunakea et al., 2010; Varley et al., 2013).”
Global Epigenomic Reconfiguration During Mammalian Brain Development (2013, background): “DNA methylation within promoter regions and in gene bodies is implicated in regulation of gene expression (22, 52), suggesting that the precisely conserved, cell type–specific DNA methylation patterns may be related to specific neuronal and glial cellular processes.”
Dynamic CpG island methylation landscape in oocytes and preimplantation embryos (2011, result): “3a,c ), similar to findings of CGI methylation in somatic tissue”