A molecular basis for B-type heterochromatic compartmental domains in mammalian interphase nuclei.

Faculty Development Competitive Research Grant Program 2021-2023

In mammals, two meters of DNA must be folded into the confines of a nucleus that is only five millionths of a meter in diameter. A measure of folding can be assessed by Hi-C, a high-throughput technique that generates contact frequency (Hi-C) maps [1]. Hi-C maps revealed that mammalian DNA is folded into compartmental domains, where A-type compartments represent euchromatin and B-type compartments represent heterochromatin [1]. According to current concepts HP1-containing heterochromatin-like complexes are likely to generate the B-type heterochromatic compartmental domains [2, 3]. The purpose of this proposal is to test this hypothesis. Specifically, our objective is to use HP1 mutant mouse embryonic stem (ES) cells to test the effect of disrupting HP1genes on the B-type heterochromatic compartmental domains observed in Hi-C maps. The proposal is entirely novel. The elucidation of the mechanism that generates the B-type compartmental domains will provide a concrete understanding of how DNA is folded into the confines of mammalian nucleus. This will have profound implications for how the mammalian genome is organized and regulated during development and disease, including viral infections e.g., COVID-19.

[1] Dekker J. and Mirny LA. The 3D genome as moderator of chromosomal communication. Cell. 2016, 164(6):1110-1121.
[2] Hildebrand EM and Dekker J, Mechanisms and Functions of Chromosome Compartmentalization. Trends in Biochemical Sciences. 2020 https://doi.org/10.1016/j.tibs.2020.01.002
[3] Singh PB and Newman AG. On the relations of phase separation and Hi-C maps to epigenetics. Royal Society Open Sci. 2020, 7: 191976.