title: Intragenic CpG islands play important roles in bivalent chromatin assembly of developmental genes.
abstract: 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.
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Sun-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Jungwoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Noh
authors.affiliation: Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Won-Young
authors.initials: WY
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Sejin
authors.initials: S
authors.lastname: Jeon
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.affiliation: Department of Integrative Bioscience and Biotechnology, College of Life Sciences, Sejong University, Seoul 05006, Republic of Korea.
authors.forename: Jeongsil
authors.initials: J
authors.lastname: Kim-Ha
authors.affiliation: Department of Biotechnology, College of Life Science and Technology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Biotechnology, College of Life Science and Technology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 03722, Republic of Korea; yjkim@yonsei.ac.kr.|Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Young-Joon
authors.identifier: 0000-0001-5061-587X
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic
chemical_list: D002843:Chromatin; D006657:Histones
keywords: DNA methylation; bivalent chromatin; differentiation; embryonic stem cell; intragenic CpG islands