Interchromosomal association and gene regulation in trans

Abstract

The nucleus is an ordered three-dimensional entity, and organization of the genome within the nuclear space might have implications for orchestrating gene expression. Recent technological developments have revealed that chromatin is folded into loops bringing distal regulatory elements into intimate contact with the genes that they regulate. Such intrachromosomal contacts appear to be a general mechanism of enhancer-promoter communication 'in cis'. Tantalizing evidence is also emerging that regulatory elements might have the capacity to act 'in trans' to regulate genes on other chromosomes. However, unequivocal data required to prove that interchromosomal gene regulation truly represents another level of control within the nucleus is still lacking, and this concept remains highly contentious. Such controversy only emphasizes that our current understanding of the mechanisms that govern gene expression are far from complete. Interchromosomal gene regulation in mammals: an emerging fieldWe are only just beginning to realize the extent of organization within the mammalian nucleus and how this might shape transcriptional regulation. Loci can interact with sequences elsewhere in the genome, leading to the hypothesis that genes can be subjected to regulation in trans by regulatory elements on other chromosomes. This concept is not without merit as a similar but well established phenomenon termed transvection takes place in Drosophila (Box 1). However, unlike classical transvection, interchromosomal gene regulation in mammals is still highly controversial. We will explore recent examples of interchromosomal associations (see Glossary) and discuss whether these represent a chance meeting of genes within the shared nuclear space or whether they provide evidence for functional regulation in trans. Nuclear organizationMore than a century ago, studies by Rabl and then Boveri suggested that chromatin was not randomly organized within the nucleus but occupied distinct regions. However, only recent advances in technology have allowed the confirmation that metaphase chromosomes are indeed organized into discrete, non-overlapping 'territories' 1 . Furthermore, chromosomes © 2010 Elsevier Ltd. All rights reserved. * Corresponding author: Department of Immunobiology, Yale University School of Medicine, 300 Cedar St. TAC S-579, New Haven, CT 06520, Phone: (203) 737-2216; Fax: (203) 737-2958, Richard.flavell@yale.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors declare that they have no financial conflict of interest.Published as : Trends Genet. 2010 April ; 26(4): 18...

Coordinated Regulation of miR-155 and miR-146a Genes during Induction of Endotoxin Tolerance in Macrophages

“…Transcriptional regulation of genes can occur in a coordinated manner to ensure simultaneous regulation. For this purpose, gene loci come in proximity and are regulated by the same transcriptional machinery (71). mir-155 has been previously shown to participate in such transcription factories upon TNF-a stimulation (72).…”

Comparing Enhancer Action in Cis and in Trans

“…However, extensive analyses based on DNA fluorescence in situ hybridization (DNA FISH) and chromatin conformation capture (3C) have shown that the threedimensional organization of the nucleus involves physical interactions between distant genomic regions, suggesting that gene regulation is more complex than this simplified model (reviewed by Gondor and Ohlsson 2009;Naumova and Dekker 2010). Further complicating our view, long-distance interactions are not limited to genomic regions on the same chromosomes (in cis), but are also observed between specific loci on separate chromosomes (in trans) (reviewed by Williams et al 2010). Through genome-wide 3C-based approaches, extensive interchromosomal interactions have been identified in yeast (Duan et al 2010), Drosophila (Sexton et al 2012), mice (Zhang et al 2012), and humans (LiebermanAiden et al 2009) and are thus a component of nuclear organization in diverse organisms.…”

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