Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Whitelaw, Nadia C., Chong, Suyinn, Morgan, Daniel K., Nestor, Colm, Bruxner, Timothy J., Ashe, Alyson, Lambley, Eleanore, Meehan, Richard and Whitelaw, Emma (2010) Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise. Genome Biology, 11 11: . doi:10.1186/gb-2010-11-11-r111


Author Whitelaw, Nadia C.
Chong, Suyinn
Morgan, Daniel K.
Nestor, Colm
Bruxner, Timothy J.
Ashe, Alyson
Lambley, Eleanore
Meehan, Richard
Whitelaw, Emma
Title Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise
Journal name Genome Biology   Check publisher's open access policy
ISSN 1474-7596
1474-760X
Publication date 2010-11-19
Sub-type Article (original research)
DOI 10.1186/gb-2010-11-11-r111
Open Access Status DOI
Volume 11
Issue 11
Total pages 10
Place of publication London, United Kingdom
Publisher BioMed
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article number R111

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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