Genome activity (e.g. transcription, replication) is in part regulated at the chromatin level via the controlled deposition of biochemical modifications of DNA or histone tails, the so-called epigenomic or epigenetic marks. These modifications may accumulate along the genome to form contiguous epigenomic domains of various size and composition. The assembly of these regions, either active/early-replicating or inactive/late-replicating, is believed to be conducted by generic principles involving the combined action of various chromatin regulators 6, 7, 8 (Figure 1a). Indeed, the de novo establishment of epigenomic states proceeds by sequence-specific recruitment of histone-modifying enzymes (HMEs). Upon initiation, modifications may then propagate locally around the initiation sites. The ‘reader–writer’ capacity of some HMEs to be also recruited (‘reader’) by the epigenomic mark they catalyze (‘writer’) results in a cooperative positive feedback loop that enables the further spreading of the mark, thus leading to the formation of chromatin domains that can be stably retained across multiple cell divisions — even in the absence of any external stimuli. However, the detailed spreading mechanisms underlying the long-range propagation of epigenetic marks far from the HME recruitment sites, along with the molecular processes driving the maintenance of a stable epigenomic memory, remain unclear.
In the last 15 years, several experimental evidences suggested that the 3D chromosome organization may be a central player in the regulation of the epigenome. Indeed, the spatial compartmentalization of the genome into 3D structures, such as the so-called A/B compartments and topologically associated domains (TADs) observed in Hi-C experiments (Figure 1b), or heterochromatic chromocenters, Polycomb foci, and transcription factories visible by microscopy, is strongly associated with epigenomics 9, 10, 11, 12. In particular, the formation of these 3D patterns is often thought to be driven by architectural proteins (e.g. HP1, PRC1) that specifically bind to the given epigenomic marks 13, 14, 15, 16, 17. Loci carrying the same epigenetic marks often tend to be colocalized (more contacts than expected) and spatially segregated (less contacts than expected) from regions having a different epigenomic content (Figure 1b) [9]. Interestingly, genomic regions localized inside compact 3D domains (e.g. a TAD with a high number of self-contacts) exhibit epigenetic profiles that are more extended than loci inside weakly compacted regions (Figure 1b right) [18]. All this suggests that there exists a coupling between the 3D chromosome organization and the epigenome regulation (Figure 1c): (i) genome folding may impact the formation of epigenomic domains along the genome as it can bring in close spatial proximity two distant loci and favor the 3D, long-range spreading of an epigenomic mark; and (ii) a given epigenomic mark may impact genome folding via the recruitment of architectural proteins. This potential feedback loop between epigenomics and 3D genome strengthens the hypothesis that 3D genome folding is key to chromatin-state assembly and maintenance.
Testing this hypothesis experimentally remains very challenging as it would involve the combined perturbations of many factors that often have several functions. Therefore, over the years, biophysical modeling has played an important role to infer the generic mechanistic rules of epigenome regulation, in particular its relation to chromosome organization. In the following, we review the various theoretical approaches that have been developed to study such an interplay between epigenomics and the 3D genome.
留言 (0)