Date Published: March 13, 2019
Publisher: Public Library of Science
Author(s): Kamel Jabbari, Johannes Wirtz, Martina Rauscher, Thomas Wiehe, Arthur J. Lustig.
Recent findings established a link between DNA sequence composition and interphase chromatin architecture and explained the evolutionary conservation of TADs (Topologically Associated Domains) and LADs (Lamina Associated Domains) in mammals. This prompted us to analyse conformation capture and recombination rate data to study the relationship between chromatin architecture and recombination landscape of human and mouse genomes. The results reveal that: (1) low recombination domains and blocks of elevated linkage disequilibrium tend to coincide with TADs and isochores, indicating co-evolving regulatory elements and genes in insulated neighbourhoods; (2) double strand break (DSB) and recombination frequencies increase in the short loops of GC-rich TADs, whereas recombination cold spots are typical of LADs and (3) the binding and loading of proteins, which are critical for DSB and meiotic recombination (SPO11, DMC1, H3K4me3 and PRMD9) are higher in GC-rich TADs. One explanation for these observations is that the occurrence of DSB and recombination in meiotic cells are associated with compositional and epigenetic features (genomic code) that influence DNA stiffness/flexibility and appear to be similar to those guiding the chromatin architecture in the interphase nucleus of pre-leptotene cells.
More than three decades ago, a relationship between genome organization and recombination was detected from banding of human chromosomes. R bands and G/R borders were found to be the preferred sites of DNA exchanges and the “hot spots” of mitotic chiasmata [1,2]. These observations suggested a correlation of recombination with compositional discontinuities (change of GC% along chromosomes) [3–5], which was later extended and statistically validated .
Although the occurrence of hot spots of recombination and its relation to open chromatin was suspected many decades ago, the recent observation of the correspondence between isochores and TADs, and the large number of available genomic maps allowed us to re-visit the recombination landscape in mammals and connect it to chromatin architecture. We have shown that the majority of low recombination domains coincides with pre-leptotene constitutive LADs (the GC-poorest, transcriptional repressed isochores). Our data suggests that the trade-off between major determinants of the genomic code, namely DNA sequence constraints and the associated modified or native protein binding partners, can affect the conformation of the chromatin fibre, primarily determined by its own stiffness and flexibility. LRDs and LD-blocks are shown to significantly, albeit weakly, match TADs and isochores. Moreover, loading and binding affinities of key determinants of meiotic recombination hot spots (PRMD9, SPO11, DMC1, H3K4me3) are positively correlated with TADs GC%. Combined, these observations suggest that DSB and recombination frequencies are associated with similar compositional and epigenetic features that constrain the distribution of chromatin in the interphase nucleus. Pre-meiotic TADs and sub-TADs and their sequence design (e.g. oligonucleotide frequencies) might represent a structural template, within which meiotic loops organize themselves, evoking a component not yet taken into consideration in the “topological memory” paradigm.