Human Histone Interaction Networks: An Old Concept, New Trends

Abstract

To elucidate the properties of human histone interactions on the large scale, we perform a comprehensive mapping of human histone interaction networks by using data from structural, chemical cross-linking and various high-throughput studies. Histone interactomes derived from different data sources show limited overlap and complement each other. It inspires us to integrate these data into the combined histone global interaction network which includes 5308 proteins and 10,330 interactions. The analysis of topological properties of the human histone interactome reveals its scale free behavior and high modularity. Our study of histone binding interfaces uncovers a remarkably high number of residues involved in interactions between histones and non-histone proteins, 80-90% of residues in histones H3 and H4 have at least one binding partner. Two types of histone binding modes are detected: interfaces conserved in most histone variants and variant specific interfaces. Finally, different types of chromatin factors recognize histones in nucleosomes via distinct binding modes, and many of these interfaces utilize acidic patches among other sites. Interaction networks are available at https://github.com/Panchenko-Lab/Human-histone-interactome.

Keywords: histone; interaction; interactome; network; nucleosome.

Figure 1.

A workflow to construct human histone interactomes from different resources using PDB structures of histone complexes, crosslinking mass spectrometry and high-throughput data from the APID database.

Figure 2.

Human histone interactions at different granularity levels. The protein-level and domain-level networks are shown as the preferred layout in Cytoscape and nodes of histones and histone-binding proteins are colored as green and pink while hub nodes in histone binding proteins (nodes with the high node degree) are highlighted as orange. Degree sorted circle layout in Cytoscape is applied to show the residue-level interactions, where histone residues are colored by purple, yellow, red, blue and green per histone colour convention while binding proteins are shown as pink nodes.

Figure 3.

Topological properties of human histone interactomes. a) Partners which interact with histone-binding proteins are identified (orange nodes) and added as one additional layer to the initial networks (green and pink nodes) to construct histone global interactomes. b) and c) Comparison of the network topological properties between structural, cross-linking and high-throughput global interactomes.

Figure 4.

Functional classification of histone-binding proteins in the global histone interactomes at protein level. Proteins were classified using PANTHER classification system (ten top ranked protein types are shown) and categorized by PANTHER protein classes. Histones are represented as large green rectangular nodes while binding proteins are shown as circular nodes and colored by their functions. Proteins which cannot be clearly classified by PANTHER protein classes are colored by grey. The hubs nodes of the networks (MCC score >=4) are highlighted as middle size squares.

Figure 5.

Mapping of protein binding sites onto human histones using the data extracted from structural and cross-linking interactomes. a) The number of binding proteins per residue mapped onto the consensus sequence of the full alignment of human histone sequences (see Figure SM 9, 13–17). Red asterisks denote acidic patches and globular domains are indicated by purple, yellow, red, blue and green bars per histone colour convention. The full sequence alignment of H2A variants contains residue 1 to 378 (Figure SM 14) and the plot only shows the region of 1 to 200 which has the vast majority of histone interactions. b) Binding hotspots are highlighted on histone structures. Binding hotspots are defined if a residue interacts with more than five different proteins. H1 structure is taken from PDB: 4QLC and structures of H2A, H2B, H3 and H4 are from PDB: 1KX5. We illustrate H1 C-and N-terminal tails by linearly extending them since they are not resolved in the structures.

Figure 6.

Mapping of protein binding sites on human histones within nucleosomes. The nucleosome-binding proteins are classified by their functions using the PATHNER classification system (all PDB IDs are provided in Table SM10). The nucleosome representation is generated from PDB 1KX5 and histones are colored by yellow, pink, light blue and light green per histone colour convention. The binding interfaces are colored according to the categories in the pie chart. Acidic patch is marked with a red circle.