title: Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise.
abstract: BACKGROUND
  Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.
  
  
  RESULTS
  Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.
  
  
  CONCLUSIONS
  These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans.
authors.affiliation: Genetics and Population Health, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.
authors.forename: Nadia C
authors.initials: NC
authors.lastname: Whitelaw
authors.forename: Suyinn
authors.initials: S
authors.lastname: Chong
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Morgan
authors.forename: Colm
authors.initials: C
authors.lastname: Nestor
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bruxner
authors.forename: Alyson
authors.initials: A
authors.lastname: Ashe
authors.forename: Eleanore
authors.initials: E
authors.lastname: Lambley
authors.forename: Richard
authors.initials: R
authors.lastname: Meehan
authors.forename: Emma
authors.initials: E
authors.lastname: Whitelaw
mesh_terms: D000483:Alleles; D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005260:Female; D020868:Gene Silencing; D014644:Genetic Variation; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C000715470:MAS1 protein, human; C000715471:Mas1 protein, mouse; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28