A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development

Ashe, Alyson, Morgan, Daniel K., Whitelaw, Nadia, Bruxner, Timothy J., Vickaryous, Nicola K., Cox, Liza L., Butterfield, Natalie C., Wicking, Carol, Blewitt, Marnie E., Wilkins, Sarah J., Anderson, Gregory J., Cox, Timothy C. and Whitelaw, Emma (2008) A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biology, 9 12: R182-1-R182-16. doi:10.1186/gb-2008-9-12-r182

Author Ashe, Alyson
Morgan, Daniel K.
Whitelaw, Nadia
Bruxner, Timothy J.
Vickaryous, Nicola K.
Cox, Liza L.
Butterfield, Natalie C.
Wicking, Carol
Blewitt, Marnie E.
Wilkins, Sarah J.
Anderson, Gregory J.
Cox, Timothy C.
Whitelaw, Emma
Title A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development
Journal name Genome Biology   Check publisher's open access policy
ISSN 1474-760X
Publication date 2008-12-19
Sub-type Article (original research)
DOI 10.1186/gb-2008-9-12-r182
Open Access Status DOI
Volume 9
Issue 12
Start page R182-1
End page R182-16
Total pages 16
Place of publication London, United Kingdom
Publisher Biomed Central
Language eng
Formatted abstract
Some years ago we established an N-ethyl-N-nitrosourea screen for modifiers of transgene variegation in the mouse and a preliminary description of the first six mutant lines, named MommeD1-D6, has been published. We have reported the underlying genes in three cases: MommeD1 is a mutation in SMC hinge domain containing 1 (Smchd1), a novel modifier of epigenetic gene silencing; MommeD2 is a mutation in DNA methyltransferase 1 (Dnmt1); and MommeD4 is a mutation in Smarca 5 (Snf2h), a known chromatin remodeler. The identification of Dnmt1 and Smarca5 attest to the effectiveness of the screen design.


We have now extended the screen and have identified four new modifiers, MommeD7-D10. Here we show that all ten MommeDs link to unique sites in the genome, that homozygosity for the mutations is associated with severe developmental abnormalities and that heterozygosity results in phenotypic abnormalities and reduced reproductive fitness in some cases. In addition, we have now identified the underlying genes for MommeD5 and MommeD10. MommeD5 is a mutation in Hdac1, which encodes histone deacetylase 1, and MommeD10 is a mutation in Baz1b (also known as Williams syndrome transcription factor), which encodes a transcription factor containing a PHD-type zinc finger and a bromodomain. We show that reduction in the level of Baz1b in the mouse results in craniofacial features reminiscent of Williams syndrome.

These results demonstrate the importance of dosage-dependent epigenetic reprogramming in the development of the embryo and the power of the screen to provide mouse models to study this process.
Keyword Position-effect Variegation
Nitrosourea enu Screens
Histone Deacetylase
Craniofacial Development
Epigenetic Inheritance
Coding Mutations
Agouti Locus
Human Hdac8
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 52 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 55 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 16 Apr 2009, 14:32:53 EST by Sarah Elliott on behalf of Faculty Of Health Sciences