title: Intermediate DNA methylation is a conserved signature of genome regulation.
abstract: The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage.
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: GiNell
authors.initials: G
authors.lastname: Elliott
authors.affiliation: Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94115, USA.
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: 1] Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94115, USA [2] Institute for Human Genetics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Bell
authors.affiliation: Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Maire
authors.affiliation: Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94115, USA.
authors.forename: Mahvash
authors.initials: M
authors.lastname: Sigaroudinia
authors.affiliation: Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94115, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gascard
authors.affiliation: Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94115, USA.
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.affiliation: School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK.
authors.forename: Leonard C
authors.identifier: 0000000170305756
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Misha
authors.initials: M
authors.lastname: Bilenky
authors.affiliation: 1] Social Genetic &Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London WC2R 2LS, UK [2] University of Exeter Medical School, Exeter University, St Luke's Campus, Exeter EX1 2LU, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Department of Pharmacology and the Genome Center, University of California-Davis, Davis, California 95616, USA.
authors.forename: Peggy J
authors.identifier: 0000000344697914
authors.initials: PJ
authors.lastname: Farnham
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
authors.affiliation: 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [2] Centre for High-Throughput Biology and Department of Microbiology &Immunology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
authors.forename: Martin
authors.identifier: 0000000191369054
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Stormo
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94115, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
mesh_terms: D000818:Animals; D019175:DNA Methylation; D057890:Epigenomics; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D015894:Genome, Human; D042421:Histone Code; D006801:Humans; D051379:Mice; D026801:Synteny