“…Provided with the extensive understanding of roles of nuclear proteins and nucleome organization, it still remains mysterious about how these nuclear proteins collectively partition, interact and organize in nucleome to drive and mediate the dynamic changes of chromosomal folding, 3-D genome organization, the assembly of nuclear body, the formation of biomolecular condensate and HUB of chromatin-RNA interactions, the histone code encryption and code-deciphering and regulation of gene expression. To address some of these questions from a different perspective, we decided to combine the in vivo chemical crosslinking-coupled mass spectrometry (XL-MS) (Iacobucci et al, 2019;Liu et al, 2018b;Yu and Huang, 2018) with a MONET-based (Tomasoni et al, 2020) modulomics to profile nucleomic protein-protein interactions (PPIs) and construct a nuclear protein interaction modulome, consisting of hierarchically and topologically organized protein clusters, complexes, subnuclear compartments (including nucleoli, nuclear condensates and nuclear bodies) and nucleosomes. The in vivo formaldehydefixing of interacting DNA molecules in living cells had been successfully applied in the proximity ligation of DNA fragments (3C, chromatin conformation capture; Hi-C, highthroughput chromosome conformation capture) to elucidate the comprehensive 3-D genome topology and chromatin fiber interactions (Dekker et al, 2002;Nagano et al, 2013;Quinodoz et al, 2018) and to reveal high resolution architecture features and dynamic changes of chromatin loops and TADs in genome organization (Dekker and Mirny, 2016;Lieberman-Aiden et al, 2009;Misteli, 2020).…”