|
|
Imprinting, Transcription Factories, and Igf2 Regulation« Back to Volume 22, Issue 3, September 2006 - Table of Contents An important regulator of fetal growth, insulin-like growth factor 2 (Igf2), has received much attention in recent years because it is imprinted, ie, expressed only from the paternal allele, in contrast to the Igf2 receptor, which is expressed only from the maternal allele. New clues regarding regulation of Igf2 expression have emerged as further insight is gained into how gene expression is regulated in general and how DNA and chromosomes are organized in the nucleus. As commented upon by Spilinakis and Flavell, DNA in higher organisms is organized with nucleoproteins into different kinds of chromatin from which chromosomes are constructed. Each chromosome resides in a specific region of the nucleus except during cell division. Genes being actively expressed typically loop out from condensed chromatin into regions called “transcription factories” where the transcriptional machinery including factors that initiate and regulate transcription resides. Conventionally, this process was thought to be controlled by regulatory elements on the same chromosome as the gene being regulated—so-called cis regulation. However, there is growing evidence for genes on one chromosome being regulated by regulatory elements located on a different chromosome, ie, trans regulation, and this may help to explain the control of Igf2 expression. A publication by Ling et al shows that a maternal gene locus on (mouse) chromosome 7 harboring 2 adjacent imprinted genes localizes with a paternal locus on chromosome 11 containing different genes in a manner that depends on a protein termed CTCF (CCCTC-binding factor). Interchromosomal rendezvous. The interaction between two different gene loci on two different chromosomes is mediated by the transcriptions regulatory factor CTCF and -perhaps other factors. This may occur on regions of the nucleus that are enriched with transcription machinery whereby the genetic elements on one chromosome regulate expression of genes on the partnering chromosome. More specifically, Igf2 and H19 are coordinately regulated, imprinted genes located ~ 80 kb apart on mouse chromosome 7 (Figure). An imprinting control region (ICR) located between them contains 4 binding regions for CTCF, a zinc finger-binding protein. Using a technique called chromosome conformation capture combined with fluorescence in situ hybridization, Reik and colleagues recently demonstrated that on the paternal chromosome, a differentially methylated region (DMR) loops out to interact with the methylated ICR pushing the Igf2 promoter into contact with the H19 enhancer resulting in Igf2 expression.1 On the maternal chromosome, a DMR interacts with the unmethylated ICR, partitioning the Igf2 promoter into a silent loop. Ling et al applied additional assays to show an interaction of DNA sequences mapped to ICR between the Igf2 and H19 loci on chromosome 7 with sequences that mapped to a region located between 2 genes—Wsb1 and Nf1—on chromosome 11, which they called the ICR-associated site. They showed that CTCF binds only to the maternal allele of the Igf2 ICR and only to the paternal allele of ICR-associated site on chromosome 11 and that these specific interactions are required for co-localization and presumed interaction of relevant intrachromosomal loops from chromosomes 7 and 11. Ling et al caution that while they cannot be certain, their evidence strongly argues that the genes on chromosomes 7 and 11 physically interact and regulate each other’s expression. They note that transcription factories rich in preassembled transcription complexes are presumed to exist within the nucleus and suggest that since there are most likely fewer factories than transcribed genes, some genes would need to share a common factory. Given the strict parental allele specificity of CTCF binding, they further suggest that interchromosomal association plays an important role in the imprinting process. Spilianakis and Flavell propose in their commentary that interchromosomal interactions may be a general phenomenon in gene regulation. Editor’s Commenthese papers add another chapter to the saga of imprinting and further insights into the complexity of gene regulation in higher organisms. It almost makes one long for the days when regulation could be explained one gene at a time with a relatively small number of transcription factors that turned them on and off. The new insights, however, provide a means to begin to explain observations, such as variable expression of genetic disease that we have never understood very well. William A. Horton, MD Reference - (linked to
|
Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
)