3.4 │ Networks of histone H1 subtypes-partner proteins
interactions
Networks of histone H1 subtypes-partner proteins interactions were
extracted from STRING database (v11.0) and introduced to the Cytoscape
software (v3.8.0) for further analysis. A comparison of several
topological parameters obtained by MCM function of Network Analyzer
plugin indicate on an overall similarity of the networks (F =
0.613, p = 0.654) (Table 4). Although that some of analyzed
topological parameters, such as characteristic path length, clustering
coefficient, centralization and heterogeneity, possess the roughly
similar numeric values, the differences are noticeable among the others.
Because the networks sizes are defined ambiguously, e.g. small sized
contain less than 10 – 20 nodes 29, small- and medium
sized contain 50 – 500 nodes 30 and small to large
sized contain 100 – 1000 nodes 31, a concrete
determination of H1 networks scales is rather intuitive because they
differ three to four times on average. The subtype H1.1, H1.2 and H1.4
(126, 86 and 92 nodes) belong to greater networks compared to small
scale networks of subtype H1.3 and H1.5 (30 and 47 nodes). Likewise, a
network connectivity expressed by the average number of neighbors also
differentiate the histone H1 subtype-interacting protein networks. The
average connectivity of node, strongly related to the network resilience32, is about two and three times higher in the network
of subtype H1.1 (13.872) and H1.4 (11.525) than in the network of
subtype H1.5 (6.718) and H1.3 (3.6). These values characteristic of
subtype H1.3 and H1.5 interaction network are also lower that of the
subtype H1.2 (9.02). This indicate that the networks created by histone
H1 subtypes differ in their compaction. Because highly connected nodes
do not have a higher density 33, the networks of
subtype H1.1, H1.2 and H1.4 are more sparse than that of more dense of
subtype H1.3 and H1.5. Another parameter, i.e. connected components
indicating a connectivity of the network, is comparable for the networks
of subtype H1.2, H1.3, H1.4 and H1.5 (in the range from 8 to 12), but
its value is much lower (amounting 3) for the network created by histone
H1.1. This pointing to a stronger connectivity of H1.1 subtype network
compared to the networks of subtypes H1.2 – H1.5 34and simultaneously reflecting their tendency to an increased
fragmentation to the separated clusters. 35 Most
relevant neighborhood of histone H1 in the networks were identified by
construction the active subnetworks using Diffusion algorithm of
Cytoscape. In the vast majority, they contain proteins which GO terms
that were predicted by CELLO2GO as associated with processes involved in
the metabolism of DNA and regulation of its activity. It seems that in
the DNA-dependent processes histone H1 subtypes displays a similar
activity realized, however, by interactions with different proteins. The
only one protein, i.e. DNA fragmentation factor subunit beta, turned out
to be a component of subnetworks formed by subtypes H1.1, H1.3 and H1.5
(Table 5).
To find a highly connected nodes (hub proteins) with essential
biological properties in the histone H1 subtypes-protein interaction
networks, the MCM method of cytoHubba plugin was adopted. With the help
of this tool, a top hub proteins of the networks were ranked (Table 6).
An overview of the functions of selected proteins allow to designate the
cell processes in which histone H1 subtypes might operate in common with
their partnering proteins. Based on a similarity of molecular function
and biological process of identified hubs, the histone H1 subtypes may
be divided into three categories. First class includes subtypes H1.1 and
H1.4 having five common proteins which, just like other top hubs, are
involved in the RNA binding and biogenesis of ribosome. Second class
contain subtypes H1.3 and H1.5 possessing three same proteins engaged in
the control and regulation of cell cycle as well as in the cell
division, similarly to the rest of the hubs. Third class encompass a
single subtype H1.2 interacting with proteins responsible of protein
ubiquitination and degradation. It should be noticed that among five
histone H1 subtypes, the only subtype H1.3 was designated as a hub in
the network. This suggest its critical role in the maintenance of the
network structure. 36 Thus, according to the
centrality-lethality rule 37, histone H1.3 may be
recognized as functionally significant since its lack may disturb a
pathway function. 38 Moreover, a comparison of
topological parameters values presented in the Table 6, indicated a
disparity between the network constructed with subtype H1.1 and the
networks created with subtype H1.3 and H1.5. A statistically significant
difference was determined for a closeness centrality (H1.1 – H1.3 p
< 0.05 and H1.1 – H1.5 p < 0.01), clustering
coefficient (H1.1 – H1.3 p < 0.05 and H1.1 – H1.5 p
< 0.05) and a neighborhood connectivity (H1.1 – H1.3 p
< 0.001 and H1.1 – H1.5 p < 0.001). Such a
distinctions between the networks hubs suggest functional dissimilarity
between histone H1.1 and histone H1.3 and H1.5.