Are genes switched on when they kiss?

Abstract

Chromatin loops are pervasive and permit the tight compaction of DNA within the confined space of the nucleus. Looping enables distal genes and DNA elements to engage in chromosomal contact, to form multigene complexes. Advances in biochemical and imaging techniques reveal that loopmediated contact is strongly correlated with transcription of interacting DNA. However, these approaches only provide a snapshot of events and therefore are unable to reveal the dynamics of multigene complex assembly. This highlights the necessity to develop single cell-based assays that provide single molecule resolution, and are able to functionally interrogate the role of chromosomal contact on gene regulation. To this end, high-resolution single cell imaging regimes, combined with genome editing approaches, are proving to be pivotal to advancing our understanding of loop-mediated dynamics.

Small chromosomal regions position themselves autonomously according to their chromatin class

“…In case of interspersed repeats, the players remain unknown, and we can only speculate that they might be represented by such epigenetic cues as noncoding RNAs or chromatin proteins recognizing methylated DNA and posttranslational histone modifications. In accordance with this, recent studies suggest that recognition sequences for nuclear proteins can cause differential association of active chromatin with transcription factors, promoters and enhancers, and splicing machinery, and thus facilitate their clustering (Mitchell and Fraser 2008;Schoenfelder et al 2010;Fanucchi et al 2013Fanucchi et al , 2014Tang et al 2015). Similarly, clustering of inactive chromatin is mediated by associating with proteins involved in heterochromatin formation and maintenance, such as histone deacetylases, histone methyltransferases, DNA methylases, Polycomb group proteins, HP1, and many others (Denholtz et al 2013;Smith and Meissner 2013;Ciabrelli and Cavalli 2015;Schubeler 2015;Vieux-Rochas et al 2015;Soshnev et al 2016).…”

Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More?

“…The interplay between histone marks and DNA methylation pattern can result in the organization of actively transcribed loci in transcriptional factories ( 46 ), demonstrating the influence of epigenetic marks on genome topology. Recently, emerging evidence suggests that higher order interactions between chromosomal regions in cis and trans might impose further influence on gene expression ( 47 , 48 ). Importantly, stochastic interchromosomal interactions can account for gene expression heterogeneity in a population: for example, co-localization of β-globin gene and its enhancer was observed in 5–10% of cells in a population and correlated with a ~100-fold increase of β-globin expression in these “jackpot” cells ( 49 ).…”

Chromosome dynamics and folding in eukaryotes: Insights from live cell microscopy

“…However, the probability that the snapshot of a single cell at the moment of fixation or imaging is representative of a meaningful event can be very low, because many events are very short lived. This is illustrated by the small percentage (5%) of imaged nuclei in which Fanucci et al detected colocalization of three mRNA signals from co-regulated genes using in situ hybridisation [81]. In order to detect rare events and, more importantly, enable statistically significant comparison of data in different conditions and cell types, high throughput imaging techniques with sufficient resolution to detect point like signals (spots) in 3D (Fig.…”