Interchromosomal interactions: A genomic love story of kissing chromosomes

Abstract

Nuclei require a precise three- and four-dimensional organization of DNA to establish cell-specific gene-expression programs. Underscoring the importance of DNA topology, alterations to the nuclear architecture can perturb gene expression and result in disease states. More recently, it has become clear that not only intrachromosomal interactions, but also interchromosomal interactions, a less studied feature of chromosomes, are required for proper physiological gene-expression programs. Here, we review recent studies with emerging insights into where and why cross-chromosomal communication is relevant. Specifically, we discuss how long noncoding RNAs (lncRNAs) and three-dimensional gene positioning are involved in genome organization and how low-throughput (live-cell imaging) and high-throughput (Hi-C and SPRITE) techniques contribute to understand the fundamental properties of interchromosomal interactions.

Figure 1.

Interchromosomal interactions are a substantial part of genome organization and biological processes. (A) The interphase genome (1; Hoechst staining) consists of chromosomal territories (2) that share intermingling chromosomal regions in the 3D space of the nucleus. (3) Chromatin strands can loop out of their chromosomal territory and facilitate the formation of transcription factories. (B) The nucleus is organized in subnuclear compartments (e.g., speckles and nucleolus). In humans, five chromosomes are positioned around the nucleolus. (C) Intermingling chromosomal territories with highly specific NHCCs form the olfactosome to drive exclusive monogenic and mono-allelic OR gene expression. (D) Left: Heterochromatic foci appear as dense regions in the interphase genome, while dark (less dense) spots indicate less condensed chromatin. (1) Heterochromatic foci with H3K9me3 histone marks and silent gene loci can colocalize in the nucleus. (2) Transcription factors (TFs) facilitate the regulation of gene expression in tissue-specific transcription factories, where intermingling loci are in close spatial proximity.

Figure 2.

LncRNA loci and their NHCCs, and mechanistic principles of NHCCs. (A) The lncRNA locus FIRRE interacts with ATF4 and YPEL4 in human cells. This 3D organization is conserved in the mouse genome, where Firre also interacts with Slc25a12, Eef1a1, and Ppp1r10. (B) The regulatory lncRNA locus CISTR-ACT facilitates 3D proximity to PTHLH, and the NHCC with SOX9, in normal cells. When balanced translocations disrupt this interaction and misplace CISTR-ACT onto a derivative chromosome, the positional effect leads to down-regulated PTHLH and SOX9 and up-regulated CISTR-ACT. (C) CLING determined that NHCCs have an average proximity of ∼279 ± 163 nm, while intrachromosomal interactions were 189 ± 95 nm apart. DNase I hypersensitivity sites (DHS) and convergent CTCF motifs are features of gene regulatory regions (loop-extrusion model) that are in spatial proximity to cooperate with tissue-specific transcription factors, ncRNAs, and RBPs to regulate the expression of genes that are located on different chromosomes (see transcription factory in Fig. 1 A).

Figure 3.

Exploring NHCCs toward understanding their contribution to gene regulation and genome organization in health and disease. (A) SNP-CLING enables the study of allele-specific locus positioning and spatiotemporal dynamics in living cells (depicted example: mESC with exemplified time-lapse imaging of a maternal and paternal allele and their distances to the nucleolus). (B) Left: Maternal and paternal alleles of the interphase genome are in physical proximity and intermingle to control tissue-specific gene regulation in the 3D space of the nucleus. LncRNAs, proteins (chromatin modifiers, transcription factors, etc.), biophysical properties of the chromatin, genome organization, and stochastics cooperate to contribute to variable, but specific, biological processes. Right: Structural (i.e., deletions, translocations, etc.) and numerical chromosomal aberrations (e.g., trisomies) can disrupt and reorganize the intricate network of NHCCs. These aberrations cause altered transcriptional programs, repositioning of genomic loci, and reorganization of tissue-specific gene regulation that can influence genetic and developmental processes. They comprise a variable layer of genome organization and are often associated with pathogenic pathways and disease.