title: The human placenta methylome.
abstract: Tissue-specific DNA methylation is found at promoters, enhancers, and CpG islands but also over larger genomic regions. In most human tissues, the vast majority of the genome is highly methylated (>70%). Recently, sequencing of bisulfite-treated DNA (MethylC-seq) has revealed large partially methylated domains (PMDs) in some human cell lines. PMDs cover up to 40% of the genome and are associated with gene repression and inactive chromatin marks. However, to date, only cultured cells and cancers have shown evidence for PMDs. Here, we performed MethylC-seq in full-term human placenta and demonstrate it is the first known normal tissue showing clear evidence of PMDs. We found that PMDs cover 37% of the placental genome, are stable throughout gestation and between individuals, and can be observed with lower sensitivity in Illumina 450K Infinium data. RNA-seq analysis confirmed that genes in PMDs are repressed in placenta. Using a hidden Markov model to map placental PMDs genome-wide and compare them to PMDs in other cell lines, we found that genes within placental PMDs have tissue-specific functions. For regulatory regions, methylation levels in promoter CpG islands are actually higher for genes within placental PMDs, despite the lower overall methylation of surrounding regions. Similar to PMDs, polycomb-regulated regions are hypomethylated but smaller and distinct from PMDs, with some being hypermethylated in placenta compared with other tissues. These results suggest that PMDs are a developmentally dynamic feature of the methylome that are relevant for understanding both normal development and cancer and may be of use as epigenetic biomarkers.
authors.affiliation: Department of Medical Microbiology and Immunology, UC Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: Diane I
authors.initials: DI
authors.lastname: Schroeder
authors.forename: John D
authors.initials: JD
authors.lastname: Blair
authors.forename: Paul
authors.initials: P
authors.lastname: Lott
authors.forename: Hung On Ken
authors.initials: HO
authors.lastname: Yu
authors.forename: Danna
authors.initials: D
authors.lastname: Hong
authors.forename: Florence
authors.initials: F
authors.lastname: Crary
authors.forename: Paul
authors.initials: P
authors.lastname: Ashwood
authors.forename: Cheryl
authors.initials: C
authors.lastname: Walker
authors.forename: Ian
authors.initials: I
authors.lastname: Korf
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000737:chemistry; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D017423:Sequence Analysis, RNA; D013447:Sulfites
chemical_list: D015415:Biomarkers; D002843:Chromatin; D013447:Sulfites; C042345:hydrogen sulfite