Sun-Min Leea, Jungwoo Leeb, Kyung-Min Nohc, Won-Young Choib, Sejin Jeond, Goo Taeg Ohd, Jeongsil Kim-Hae, Yoonhee Jinf, Seung-Woo Chof, and Young-Joon Kima,b,1
aDepartment of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 03722, Republic of Korea;
bDepartment of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea;
cGenome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany;
dDepartment of Life Sciences, Ewha Womans University, Seoul 03760, Republic of Korea;
eDepartment of Integrative Bioscience and Biotechnology, College of Life Sciences, Sejong University, Seoul 05006, Republic of Korea;
fDepartment of Biotechnology, College of Life Science and Technology, Yonsei University, Seoul 03722, Republic of Korea
CpG, 5′-C-phosphate-G-3′, islands (CGIs) have long been known for their association with enhancers, silencers, and promoters, and for their epigenetic signatures. They are maintained in embryonic stem cells (ESCs) in a poised but inactive state via the formation of bivalent chromatin containing both active and repressive marks. CGIs also occur within coding sequences, where their functional role has remained obscure. Intragenic CGIs (iCGIs) are largely absent from housekeeping genes, but they are found in all genes associated with organ development and cell lineage control. In this paper, we investigated the epigenetic status of iCGIs and found that they too reside in bivalent chromatin in ESCs. Cell type-specific DNA methylation of iCGIs in differentiated cells was linked to the loss of both the H3K4me3 and H3K27me3 marks, and disruption of physical interaction with promoter regions, resulting in transcriptional activation of key regulators of differentiation such as PAXs, HOXs, and WNTs. The differential epigenetic modification of iCGIs appears to be mediated by cell type-specific transcription factors distinct from those bound by promoter, and these transcription factors may be involved in the hypermethylation of iCGIs upon cell differentiation. iCGIs thus play a key role in the cell type-specific regulation of transcription.
intragenic CpG islands, DNA methylation, bivalent chromatin, embryonic stem cell, differentiation
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Author contributions: S.-M.L. and Y.-J.K. designed research; S.-M.L., J.L., K.-M.N., S.J., and G.T.O. performed research; K.-M.N., Y.J., and S.-W.C. contributed new reagents/analytic tools; S.-M.L., J.L., and W.-Y.C. analyzed data; and S.-M.L., J.K.-H., and Y.-J.K. wrote the paper.