Spatial partitioning of the regulatory landscape of the X-inactivation center

By E. Nora, B. Lajoie, Edda G. Schulz, L. Giorgetti, I. Okamoto, N. Servant, T. Piolot, Nynke L. van Berkum, Johannes Meisig, J. Sedat and 5 more. Nature, 2012

2,846 citations recorded by the source corpus.

In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/81d97d4312784cb41046e7813ae54762a5fcbc6e

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Citations in the corpus

Topologically-associating domains are stable units of replication-timing regulation (2014, neutral): “Recent Hi-C mapping has unveiled a substructure of topologically-associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to RDs 8,10 .”
Activation of proto-oncogenes by disruption of chromosome neighborhoods (2015, background): “Transcriptional enhancers normally interact with their target genes through the formation of DNA loops (5-7), which typically are constrained within larger CTCF-cohesin mediated loops called insulated neighborhoods (8-10), which in turn can form clusters that contribute to topologically associating ”
Comparative Hi-C Reveals that CTCF Underlies Evolution of Chromosomal Domain Architecture (2015, neutral): “Previous studies have observed a correlation between insulator binding and domain borders (Sexton et al., 2012; Dixon et al., 2012; Nora et al., 2012; Hou et al., 2012), and knockout experiments have suggested a quantitative link between loss of chromosomal looping structure and loss of the CTCF/coh”
Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes (2014, neutral): “Recent pioneering studies of mammalian chromosome structure have suggested that they are organized into a hierarchy of units, which include Topologically Associating Domains (TADs) and gene loops (Figure 1A)(Dixon et al., 2012; Filippova et al., 2014; Gibcus and Dekker, 2013; Naumova et al., 2013; N”
Statistical confidence estimation for Hi-C data reveals regulatory chromatin contacts (2014, result): “We also tested whether our confidence estimates are consistent with recent models that suggest chromatin is organized into megabase-sized topological domains (Dixon et al. 2012; Nora et al. 2012).”
Editing DNA methylation in the mammalian genome (2016, neutral): “…are constrained within larger CTCF-mediated loops called insulated neighborhoods (Dowen et al., 2014; Ji et al., 2016; Phillips-Cremins et al., 2013), which, in turn, can form clusters of loops that contribute to topologically associating domains (TADs) (Dixon et al., 2012; Nora et al., 2012).”
Cohesin loss eliminates all loop domains (2017, background): “…the anchors of loops (Rao et al., 2014; Splinter et al., 2006) and the boundaries of contact domains (also called “topologically constrained domains”, “topologically associated domains”, or “physical domains”) (Dixon et al., 2012; Lieberman-Aiden et al., 2009; Nora et al., 2012; Rao et al., Cell.”
Long noncoding RNAs: Cellular address codes in development and disease (2013, neutral): “Large portions of the genome are partitioned into topological domains of chromatin interaction ranging from hundreds of kilobases to megabases (the resolution of current methods), within which the genes tend to be more coregulated (Dixon et al., 2012; Nora et al., 2012).”
Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, background): “…the chromosome into ‘‘regulatory neighborhoods’’ by limiting the activity of cis-regulatory elements to genes that fall within the same TAD and by preventing spreading of heterochromatic marks (Dixon et al., 2012; Nora et al., 2012) (Figures 3B and 3C, also discussed in more detail below).”