tailieunhanh - Báo cáo y học: "Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic nois"

Tham khảo luận văn - đề án 'báo cáo y học: "reduced levels of two modifiers of epigenetic gene silencing, dnmt3a and trim28, cause increased phenotypic nois"', luận văn - báo cáo phục vụ nhu cầu học tập, nghiên cứu và làm việc hiệu quả | Whitelaw et al. Genome Biology 2010 11 R111 http 2010 11 11 R111 Genome Biology RESEARCH Open Access Reduced levels of two modifiers of epigenetic gene silencing Dnmt3a and Trim28 cause increased phenotypic noise r- s I 1 34 1 Nadia C Whitelaw Suyinn Chong Daniel K Morgan Colm Nestor Timothy J Bruxner Alyson Ashe Eleanore Lambley 1 Richard Meehan3 4 Emma Whitelaw1 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. Genomewide 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 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. Background Experiments designed to analyze the significance of genes and environment on quantitative traits using laboratory rats and mice have found that 70 to 80 of all variation is of unknown origin 1 . Gartner 2 carried out experiments over a period