title: Fine mapping genetic determinants of the highly variably expressed MHC gene ZFP57.
abstract: ZFP57 is an important transcriptional regulator involved in DNA methylation and genomic imprinting during development. Here we demonstrate that gene expression also occurs at a low level in adult peripheral blood cells and other tissues including the kidney and thymus, but is critically dependent on underlying local genetic variation within the MHC. We resolve a highly significant expression quantitative trait locus for ZFP57 involving single-nucleotide polymorphisms (SNPs) in the first intron of the gene co-localizing with a DNase I hypersensitive site and evidence of CTCF recruitment. These data identify ZFP57 as a candidate gene underlying reported MHC disease associations, notably for putative regulatory variants associated with cancer and HIV-1. The work highlights the role that ZFP57 may play in DNA methylation and epigenetic regulation beyond early development into adult life dependent on genetic background, with important potential implications for disease.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Plant
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.affiliation: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK [2] INSERM UMR-S 958, F-75010 Paris, France [3] Univ Paris Diderot, Sorbonne Paris Cité, F-75013 Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Vandiedonck
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jayachandran
authors.initials: J
authors.lastname: Radhakrishnan
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics; D000076246:CCCTC-Binding Factor; D002874:Chromosome Mapping; D019175:DNA Methylation; D003850:Deoxyribonuclease I / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D009369:Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D003850:Deoxyribonuclease I