Epigenetic regulation of development: towards a predictive mathematical modeling of three dimensional genome folding and cellular memory – EpiDevoMath

Cells of multicellular organisms share the same genome, but they are highly functionally specialized. Epigenetic inheritance involves transmission of information beyond the DNA sequence, such that the same sequence can be induced to different functional states that can be stably propagated through cell division. Much work is dedicated to understanding the mechanisms by which epigenetic components function and recent evidence suggests that gene expression is modulated by the higher-order structure of chromatin in the cell nucleus.

Recent statistical analysis of hundreds of epigenetic marks along the genome has revealed that eukaryotic chromatin is linearly organized into epigenomic domains characterized by a specific chromatin type. At the same time, high-throughput chromosome conformation capture (Hi-C) experiments have shown that chromatin is folded into what has been dubbed topologically-associating domains (TADs), which are marked by enhanced intra- and reduced inter-domain contacts. The experimental evidence suggests a strong correlation between epigenomic domains and TADs and hence a coupling between epigenetic regulation and the tridimensional chromosome architecture. However, the mechanisms behind this coupling are unknown and the lack of quantitative understanding of the folding process does not allow making predictions on how chromosome structure and genome function might react to mutations or environmental perturbations.

In the present project, we propose to address these questions with a multidisciplinary approach that will allow elucidating the mechanisms and consequence of the 3D folding of the genome.

The Cavalli, Everaers and Jost labs are leaders in their respective fields of epigenetics, of polymer physics and of computational biology. We will team up in a tight collaboration combining molecular genetics, Hi-C, ChIP-Seq and FISH experiments with mathematical modeling of the large-scale 3D folding of the chromatin fiber. We will start from the acquisition of ultra-high resolution Hi-C data, as well as single-cell Hi-C data from three different biological samples of Drosophila melanogaster. This invaluable dataset will feed knowledge based folding of a topologically constrained polymer model of the chromatin fiber where the experimentally observed contacts are imprinted onto the crumpled large-scale structure of chromatin. The resulting reconstructed ensemble of conformations will be validated with extensive FISH analysis. In the second step, we will develop heterogeneous polymer models capable of predicting chromosome folding as a function of the epigenetic state. Such models include attractive short-range interactions favoring contacts between sites carrying the same epigenetic marks. The first results from our collaboration have shown that TAD like contact patterns can indeed emerge from these epigenetically driven interactions. Statistical inference of the model parameters and of its relation to regional epigenomic landscape will be performed on our ultra-high resolution Hi-C data. Due to the close collaboration between the three groups, we will be able to test the predictive power of the models through specially designed biological experiments, where we will investigate the effects of erasing topological insulators and the consequence of chromosomal inversions, as well as, the folding of chromosomes in different Drosophila species characterized by extensive syntheny in the context of various numbers of chromosomal inversions and translocations.

Our first joint published work and new preliminary results show that our approach is effective and our goals are realistic. We believe that this project will ultimately deliver a novel understanding of genome function in the normal situation as well as in pathologies such as cancer that are known to be tightly linked to changes in nuclear architecture

Finally, we stress that this interdisciplinary projects requires review by biologists as well as physicists.