title: Genome-wide DNA methylation patterns in LSH mutant reveals de-repression of repeat elements and redundant epigenetic silencing pathways.
abstract: Cytosine methylation is critical in mammalian development and plays a role in diverse biologic processes such as genomic imprinting, X chromosome inactivation, and silencing of repeat elements. Several factors regulate DNA methylation in early embryogenesis, but their precise role in the establishment of DNA methylation at a given site remains unclear. We have generated a comprehensive methylation map in fibroblasts derived from the murine DNA methylation mutant Hells(-/-) (helicase, lymphoid specific, also known as LSH). It has been previously shown that HELLS can influence de novo methylation of retroviral sequences and endogenous genes. Here, we describe that HELLS controls cytosine methylation in a nuclear compartment that is in part defined by lamin B1 attachment regions. Despite widespread loss of cytosine methylation at regulatory sequences, including promoter regions of protein-coding genes and noncoding RNA genes, overall relative transcript abundance levels in the absence of HELLS are similar to those in wild-type cells. A subset of promoter regions shows increases of the histone modification H3K27me3, suggesting redundancy of epigenetic silencing mechanisms. Furthermore, HELLS modulates CG methylation at all classes of repeat elements and is critical for repression of a subset of repeat elements. Overall, we provide a detailed analysis of gene expression changes in relation to DNA methylation alterations, which contributes to our understanding of the biological role of cytosine methylation.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Weishi
authors.initials: W
authors.lastname: Yu
authors.affiliation: BCGC, Bioinformatics, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Carl
authors.initials: C
authors.lastname: McIntosh
authors.affiliation: Howard Hughes Medical Institute and Genome Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;
authors.forename: Ryan
authors.initials: R
authors.lastname: Lister
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, Maryland 20894, USA;
authors.forename: Iris
authors.initials: I
authors.lastname: Zhu
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Yixing
authors.initials: Y
authors.lastname: Han
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Jianke
authors.initials: J
authors.lastname: Ren
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, Maryland 20894, USA;
authors.forename: David
authors.initials: D
authors.lastname: Landsman
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Eunice
authors.initials: E
authors.lastname: Lee
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Victorino
authors.initials: V
authors.lastname: Briones
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Minoru
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Data Management Services, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA;
authors.forename: Robert
authors.initials: R
authors.lastname: Leighty
authors.affiliation: Howard Hughes Medical Institute and Genome Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ecker
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA; Leidos Biomedical Research, Inc., Basic Science Program, Frederick National Laboratory, Frederick, Maryland 21702, USA Kathrin.Muegge@nih.gov.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Muegge
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D003596:Cytosine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics*; D019175:DNA Methylation; D053595:Embryonic Stem Cells; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism; D034921:Lamin Type B / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D006657:Histones; D034921:Lamin Type B; D003596:Cytosine; D004247:DNA; D004265:DNA Helicases; C491758:lymphoid specific helicase, mouse