Journal Article

Conserved role of intragenic DNA methylation in regulating alternative promoters

Fouse, Shaun D., Hong, Chibo, Haussler, David, Xing, Xiaoyun, Delaney, Allen, Zhao, Yongjun, Schillebeeckx, Maximiliaan, Fiore, Chris, Marra, Marco A., Rowitch, David H., Nagarajan, Raman P., Nielsen, Cydney, Hirst, Martin, Jones, Steven J. M., Wang, Ting, Maunakea, Alika K., Varhol, Richard, Shchors, Ksenya, Johnson, Brett E., Thiessen, Nina, Heine, Vivi M., Ballinger, Tracy J., Bilenky, Mikhail, Costello, Joseph F., Turecki, Gustavo, D’Souza, Cletus

2010

Overview

Methylation in the genes DNA methylation plays an important role in the maintenance of cell identity through its effect on gene expression. Methylation of 5′ promoters is known to suppress gene expression, while the role of intragenic DNA methylation — where methylation occurs within the body of a gene itself — has been less extensively studied and remains controversial. A map of DNA methylation from the human brain has now been constructed with unprecedented coverage using next-generation sequencing. Integration of this map with brain tissue ChIP-sequencing for histone methylation, and gene expression in mouse and human, highlights a major role for intragenic methylation in regulating tissue-specific promoters in gene bodies, and a surprisingly minor role in 5′ promoters. The methylation of DNA in 5′ promoter regions suppresses gene expression, but what is the role of DNA methylation in the bodies of genes? Here, a map of DNA methylation is generated from human brain tissue; it is found that most methylated CpG islands are within intragenic and intergenic regions, rather than within promoters. It is proposed that intragenic methylation regulates the expression of alternative gene transcripts in different tissues and cell types. 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 1 , 2 , 3 , 4 , 5 . 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 5 , 6 , 7 , 8 , 9 , 10 . Tissue-specific intragenic methylation might reduce 3 , or, paradoxically, enhance transcription elongation efficiency 1 , 2 , 4 , 5 . Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes 11 , 12 , 13 , 14 , 15 . 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 16 . The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus 17 , 18 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/212 / 631/337/176/1988 / Animals / Biological and medical sciences / Brain / Brain - anatomy & histology / Brain - cytology / Brain - metabolism / Carrier Proteins - genetics / Cell Line / Conserved Sequence - genetics / CpG Islands - genetics / Deoxyribonucleic acid / DNA / DNA Methylation / DNA, Intergenic - genetics / DNA, Intergenic - metabolism / Frontal Lobe - metabolism / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Expression Regulation / Genes / Genetics / Genomics / Histones / Histones - genetics / Histones - metabolism / Human / Humanities and Social Sciences / Humans / Islands / letter / Male / Methylation / Mice / Mice, Inbred C57BL / Middle Aged / Molecular and cellular biology / Molecular genetics / multidisciplinary / Nerve Tissue Proteins / Organ Specificity / Physiological aspects / Promoter Regions, Genetic - genetics / Promoters (Genetics) / Properties / Science / Science (multidisciplinary) / Tissues / Transcription, Genetic - genetics / Transcription. Transcription factor. Splicing. Rna processing