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Title: Developmentally programmed 3' CpG island methylation confers tissue- and cell-type-specific transcriptional activation

Author
item DA-HAI, YU - Children'S Nutrition Research Center (CNRC)
item WARE, CAROL - University Of Washington
item WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)
item ZHANG, JIEXIN - Md Anderson Cancer Center
item CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC)
item GADKARI, MANASI - Children'S Nutrition Research Center (CNRC)
item KUNDE-RAMAMOORTHY, GOVINDARAJAN - Children'S Nutrition Research Center (CNRC)
item NOSAVANH, LAGINA M. - Children'S Nutrition Research Center (CNRC)
item SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular and Cellular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/15/2013
Publication Date: 5/1/2013
Citation: Da-Hai, Y., Ware, C., Waterland, R.A., Zhang, J., Chen, M., Gadkari, M., Kunde-Ramamoorthy, G., Nosavanh, L., Shen, L. 2013. Developmentally programmed 3' CpG island methylation confers tissue- and cell-type-specific transcriptional activation. Molecular and Cellular Biology. 33(9):1845-1858.

Interpretive Summary: Any molecular genetics textbook will tell you that DNA methylation (the addition of a methyl group) is an epigenetic switch that turns off genes. Our research show, however, that after human embryonic stem cells start to differentiate into different cell types and tissues, certain genome regions called CpG islands become methylated, turning on important genes involved in development. The methylation does not occur at the promoter region (the beginning of the gene), but at the other end called the 3’ (3 prime) region. Not only that, but using a computer algorithm to analyze large sets of DNA methylation data, we showed that as stem cells differentiate and become more specialized tissues and cells, these 3’ CpG islands become more and more methylated. This methylation regulates the activation of gene transcription (the first step in translating DNA into a blueprint that eventually becomes a protein) via a mechanism that depends on the blocking of a gene enhancer by a protein called CTCF. The finding is particularly important for shedding light on the complex roles of DNA methylation during mammalian development, and should lead to refinement of the 'textbook' view of this epigenetic modification.

Technical Abstract: During development, a small but significant number of CpG islands (CGIs) becomes methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here we used genome-wide DNA methylation microarrays to identify epigenetic changes during human embryonic stem cell (hESC) differentiation. We discovered a group of CGIs associated with developmental genes that gain methylation after hESCs differentiate. Conversely, erasure of methylation was observed at the identified CGIs during subsequent reprogramming to induced pluripotent stem cells (iPSCs), further supporting a functional role for the CGI methylation. Both global gene expression profiling and quantitative RT-PCR validation indicated opposing effects of CGI methylation in transcriptional regulation during differentiation, with promoter CGI methylation repressing and 3' CGI methylation activating transcription. By studying diverse human tissues and mouse models, we further confirmed that developmentally programmed 3' CGI methylation confers tissue- and cell-type specific gene activation in vivo. Importantly, luciferase reporter assays provided evidence that 3' CGI methylation regulates transcriptional activation via a CTCF-dependent enhancer-blocking mechanism. These findings expand the classic view of mammalian CGI methylation as a mechanism for transcriptional silencing, and indicate a functional role for 3' CGI methylation in developmental gene regulation.