Human Molecular Genetics Advance Access originally published online on September 27, 2007
Human Molecular Genetics 2008 17(1):15-26; doi:10.1093/hmg/ddm281
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Coordinated diurnal regulation of genes from the Dlk1–Dio3 imprinted domain: implications for regulation of clusters of non-paralogous genes
1 Department of Obstetrics and Gynecology 2 Department of Human Genetics 3 Laboratory of Molecular Chronobiology, Douglas Mental Health University Institute 4 Department of Psychiatry and 5 The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada 6 Department of Biological Sciences, The University of Illinois at Chicago, IL 60607, USA 7 Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA 8 Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
* To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Royal Victoria Hospital, Women's Pavilion, F3.32, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada. Tel: +1 5149341934 ext. 35906; Fax: +1 5148431662; Email: anna.naumova{at}muhc.mcgill.ca
Received May 28, 2007; Accepted September 21, 2007
The functioning of the genome is tightly related to its architecture. Therefore, understanding the relationship between different regulatory mechanisms and the organization of chromosomal domains is essential for understanding genome regulation. The majority of imprinted genes are assembled into clusters, share common regulatory elements, and, hence, represent an attractive model for studies of regulation of clusters of non-paralogous genes. Here, we investigated the relationship between genomic imprinting and diurnal regulation of genes from the imprinted domain of mouse chromosome 12. We compared gene expression patterns in C57BL/6 mice and congenic mice that carry the imprinted region from a Mus musculus molossinus strain MOLF/Ei. In the C57BL/6 mice, a putative enhancer/oscillator regulated the expression of only Mico1/Mico1os, whereas in the congenic mice its influence was spread onto Rtl1as, Dio3 and Dio3os, i.e. the distal part of the imprinted domain, resulting in coordinated diurnal variation in expression of five genes. Using additional congenic strains we determined that in C57BL/6 the effect of the putative enhancer/oscillator was attenuated by a linked dominant trans-acting factor located in the distal portion of chromosome 12. Our data demonstrate that (i) in adult organs, mRNA levels of several imprinted genes vary during the day, (ii) genetic variation may remove constraints on the influence of an enhancer and lead to spreading of its effect onto neighboring genes, thereby generating genotype-dependent expression patterns and (iii) different regulatory mechanisms within the same domain act independently and do not seem to interfere with each other.
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