title: The SNF2 family ATPase LSH promotes cell-autonomous de novo DNA methylation in somatic cells.
abstract: Methylation of DNA at carbon 5 of cytosine is essential for mammalian development and implicated in transcriptional repression of genes and transposons. New patterns of DNA methylation characteristic of lineage-committed cells are established at the exit from pluripotency by de novo DNA methyltransferases enzymes, DNMT3A and DNMT3B, which are regulated by developmental signaling and require access to chromatin-organized DNA. Whether or not the capacity for de novo DNA methylation of developmentally regulated loci is preserved in differentiated somatic cells and can occur in the absence of exogenous signals is currently unknown. Here, we demonstrate that fibroblasts derived from chromatin remodeling ATPase LSH (HELLS)-null mouse embryos, which lack DNA methylation from centromeric repeats, transposons and a number of gene promoters, are capable of reestablishing DNA methylation and silencing of misregulated genes upon re-expression of LSH. We also show that the ability of LSH to bind ATP and the cellular concentration of DNMT3B are critical for cell-autonomous de novo DNA methylation in somatic cells. These data suggest the existence of cellular memory that persists in differentiated cells through many cell generations and changes in transcriptional state.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
authors.forename: Ausma
authors.initials: A
authors.lastname: Termanis
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Torrea
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Jayne
authors.initials: J
authors.lastname: Culley
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Kerr
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ramsahoye
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK istancheva@ed.ac.uk.
authors.forename: Irina
authors.initials: I
authors.lastname: Stancheva
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism*; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D051379:Mice; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D018626:Retroelements / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D044503:5-Methylcytosine; D000251:Adenosine Triphosphatases; D004248:DNA (Cytosine-5-)-Methyltransferases; D004265:DNA Helicases; D018626:Retroelements; D000097584:DNA Methyltransferase 3B; C491758:lymphoid specific helicase, mouse