(Re)defining the human chromatome: an integrated meta-analysis of localization, function, abundance, physical properties and domain composition of chromatin proteins

The full complement of chromatin-associated proteins--collectively referred to as the chromatome--enables genome functioning in eukaryotes by participating in a wide range of physico-chemical processes. These include mediating diverse specific and non-specific intermolecular interactions, catalyzing in situ synthesis and modification of macromolecules, facilitating ATP-dependent chromatin remodeling, etc. Despite considerable progress in epigenomics and the structural characterization of many nuclear proteins and their complexes, our understanding of chromatin organization at the proteome scale remains incomplete. This gap hinders the development of a holistic view of genome regulation. In this study, we present a state-of-the-art characterization of the human chromatome based on an integrative meta-analysis of diverse data sources describing the composition, abundance, and sub-nuclear localization of chromatin proteins. This effort is complemented by original analyses of their physico-chemical properties, domain architectures, and interaction patterns. To support and streamline these analyses, we developed a reference dataset of chromatin proteins, integrated with an empirical, function-based classification ontology and an associated interactive web resource -- SimChrom -- accessible at https://simchrom.intbio.org/. The reference dataset was carefully curated by reconciling data among protein databases, localization, and mass spectrometry-based experimental studies. Sequence-based and AI-assisted structural analyses revealed previously unannotated domains within chromatin proteins that warrant experimental validation, as well as the widespread use of multivalent interaction strategies that underpin chromatin organization. Together, our findings establish a robust framework for future studies aimed at elucidating genome function through detailed analysis of protein-protein and protein-nucleic acid interactions within chromatin. KEY POINTSO_LIThe first comprehensive meta-analysis of human chromatin proteins that bridges diverse data types C_LIO_LIEstablished an interactive SimChrom framework for chromatome research available for the community C_LIO_LIIdentified functionally relevant hallmarks of chromatin protein organization C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/680841v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@899feorg.highwire.dtl.DTLVardef@b62f3corg.highwire.dtl.DTLVardef@d72419org.highwire.dtl.DTLVardef@83037d_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG