TAD boundaries are indeed enriched for elements shown to have insulator activity (such as CTCF binding sites and transcriptional start sites) ( Dixon et al., 2012), and insertions of a sensor gene on opposing sides of TAD boundaries show distinct expression patterns ( Symmons et al., 2014, Tsujimura et al., 2015). Although internal interactions within TADs can be cell-type specific and activity dependent ( Phillips-Cremins et al., 2013, Rao et al., 2014), these different findings support the role of TADs as basic structural and functional units.Ĭorrelations between regulatory and structural subdivisions of the genome suggest that TADs may constrain the range of action of enhancers, with TAD boundaries acting as functional “insulators” ( Chetverina et al., 2013, Yang and Corces, 2012). The regulatory domains defined by enhancers' range of action coincide also largely with TADs ( Symmons et al., 2014). Coordinately regulated tissue-specific enhancer-promoter pairs ( Shen et al., 2012) and associated long-range looping interactions ( Dowen et al., 2014, Jin et al., 2013) are usually comprised within TADs. Several indirect lines of evidence suggest that these self-interacting regions may represent the core units of genome regulatory architecture ( Gibcus and Dekker, 2013) a large proportion of TAD boundaries are shared between cell types ( Dixon et al., 2015) and largely preserved during evolution ( Vietri Rudan et al., 2015). These approaches have revealed not only loops between distant elements but also that mammalian genomes are partitioned into sub-megabase-sized domains referred to as topologically associating domains or TADs ( Dixon et al., 2012, Nora et al., 2012). Yet, how this proximity is established and regulated and how it influences target gene expression is still poorly understood.Ĭoncomitant with the growing appreciation of distant regulatory sequences, improved chromosome conformation capture techniques have provided insights into the three-dimensional organization of the genome and cis-interaction networks between genes and surrounding elements ( Hughes et al., 2014, Kieffer-Kwon et al., 2013, Li et al., 2012, Mifsud et al., 2015). There is strong evidence that such interactions require physical proximity ( Deng et al., 2012). Although our understanding of regulatory elements has improved tremendously in recent years, it remains unclear how enhancers find a specific target located several hundred kilobases away. Accordingly, mutations or genetic variants in distant enhancers are a significant cause of genetic diseases ( Benko et al., 2009, Bhatia et al., 2013, D'haene et al., 2009, Lettice et al., 2003) and contribute to intra-species ( Bauer et al., 2013, Smemo et al., 2014, Sur et al., 2012, Wasserman et al., 2010) and inter-species ( Prescott et al., 2015, Prud'homme et al., 2007) phenotypic variability. While the contribution of these elements to gene expression is generally difficult to estimate, enhancers located hundreds of kilobases from their target genes but essential to their expression are increasingly identified ( Sagai et al., 2009, Sagai et al., 2005, Spitz et al., 2003, Uslu et al., 2014, Wunderle et al., 1998, Zuniga et al., 2004) (reviewed in de Laat and Duboule, 2013, Visel et al., 2009). In large genomes where genomic distances per se can limit regulatory interactions, this function of TADs could be as essential for gene expression as the formation of insulated neighborhoods.Ī substantial fraction of gene regulatory elements lie at considerable distance from the nearest promoters ( ENCODE Project Consortium et al., 2012, Shen et al., 2012, Visel et al., 2007). ![]() Our data indicate that the Shh TAD promotes distance-independent contacts between distant regions that would otherwise interact only sporadically, enabling functional communication between them. In contrast, inversions disrupting the TAD altered global folding of the region and prevented regulatory contacts in a distance-dependent manner. ![]() Importantly, changing intra-TAD distances had no impact on Shh expression. We show that Shh enhancers act pervasively, yet not uniformly, throughout the TAD. Using a series of engineered chromosomal rearrangements at the Shh locus, we carried out an extensive fine-scale characterization of the factors that govern the long-range regulatory interactions controlling Shh expression. ![]() Gene expression often requires interaction between promoters and distant enhancers, which occur within the context of highly organized topologically associating domains (TADs).
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