Dataset Information

C3: connect separate connected components to form a succinct disease module.

ABSTRACT:

Background

Precise disease module is conducive to understanding the molecular mechanism of disease causation and identifying drug targets. However, due to the fragmentization of disease module in incomplete human interactome, how to determine connectivity pattern and detect a complete neighbourhood of disease based on this is still an open question.

Results

In this paper, we perform exploratory analysis leading to an important observation that through a few intermediate nodes, most separate connected components formed by disease-associated proteins can be effectively connected and eventually form a complete disease module. And based on the topological properties of these intermediate nodes, we propose a connect separate connected components (C3) method to detect a succinct disease module by introducing a relatively small number of intermediate nodes, which allows us to obtain more pure disease module than other methods. Then we apply C3 across a large corpus of diseases to validate this connectivity pattern of disease module. Furthermore, the connectivity of the perturbed genes in multi-omics data such as The Cancer Genome Atlas also fits this pattern.

Conclusions

C3 tool is not only useful in detecting a clearly-defined connected disease neighbourhood of 299 diseases and cancer with multi-omics data, but also helpful in better understanding the interconnection of phenotypically related genes in different omics data and studying complex pathological processes.

SUBMITTER: Wang B

PROVIDER: S-EPMC7531168 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

C3: connect separate connected components to form a succinct disease module.

Wang Bingbo B Hu Jie J Wang Yajun Y Zhang Chenxing C Zhou Yuanjun Y Yu Liang L Guo Xingli X Gao Lin L Chen Yunru Y

BMC bioinformatics 20201002 1

<h4>Background</h4>Precise disease module is conducive to understanding the molecular mechanism of disease causation and identifying drug targets. However, due to the fragmentization of disease module in incomplete human interactome, how to determine connectivity pattern and detect a complete neighbourhood of disease based on this is still an open question.<h4>Results</h4>In this paper, we perform exploratory analysis leading to an important observation that through a few intermediate nodes, mos ...[more]

PMID: 33008305

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Project description:The molecular complexity of genetic diseases requires novel approaches to break it down into coherent biological modules. For this purpose, many disease network models have been created and analyzed. We highlight two of them, "the human diseases networks" (HDN) and "the orphan disease networks" (ODN). However, in these models, each single node represents one disease or an ambiguous group of diseases. In these cases, the notion of diseases as unique entities reduces the usefulness of network-based methods. We hypothesize that using the clinical features (pathophenotypes) to define pathophenotypic connections between disease-causing genes improve our understanding of the molecular events originated by genetic disturbances. For this, we have built a pathophenotypic similarity gene network (PSGN) and compared it with the unipartite projections (based on gene-to-gene edges) similar to those used in previous network models (HDN and ODN). Unlike these disease network models, the PSGN uses semantic similarities. This pathophenotypic similarity has been calculated by comparing pathophenotypic annotations of genes (human abnormalities of HPO terms) in the "Human Phenotype Ontology". The resulting network contains 1075 genes (nodes) and 26197 significant pathophenotypic similarities (edges). A global analysis of this network reveals: unnoticed pairs of genes showing significant pathophenotypic similarity, a biological meaningful re-arrangement of the pathological relationships between genes, correlations of biochemical interactions with higher similarity scores and functional biases in metabolic and essential genes toward the pathophenotypic specificity and the pleiotropy, respectively. Additionally, pathophenotypic similarities and metabolic interactions of genes associated with maple syrup urine disease (MSUD) have been used to merge into a coherent pathological module.Our results indicate that pathophenotypes contribute to identify underlying co-dependencies among disease-causing genes that are useful to describe disease modularity.

Project description:Cells use different cell adhesion and communication structures to promote tissue development, maintenance of tissue integrity as well as repair and regenerative processes. Another recently discovered way of information exchange is long-distance thin cellular processes called nanotubes (NTs), mainly studied in vitro. Information on the existence and relevance of NTs in vivo is sparse. Building on two references which hint at the potential existence of longitudinally directed cell processes resembling NTs, we investigated tendons from young (3 weeks) and adult (9 weeks, 4 and 8 months) Fisher rats. Whole mounts of rat tail tendon fascicles (RTTfs) and sections of Achilles, flexor, extensor and patellar tendons were stained with Deep Red plasma membrane and DAPI nuclear stain and immunolabelled with Connexin43 (Cx43). In addition, 3-D reconstruction of serial semithin sections and TEM was used to verify the presence of NTs. We were able to demonstrate NTs as straight thin longitudinal processes (Ø 100-500 nm) reaching up to several 100 μm in length, mainly originating from lateral sheet-like cell processes or cell bodies in all tendon types investigated. NTs were observed to distend between tenocyte rows at the same level but also connect cells of different rows, thus leading to a complex 3-D cellular scaffold. Shorter NTs connected lateral cell sheets of tenocytes in the same row, omitting one or two cells. In addition, we detected links or potential branching of NTs. Cx43 immunostaining for the detection of gap junctions revealed Cx43-positive foci at the end-to-end contacts of tenocyte cell bodies as well as along their contacting sheet-like processes. Only rarely, we found clear Cx43 signals at their potential contact points between NTs and tendon cells as well as along the course of NTs, and most NTs appeared completely devoid of Cx43 signals. Therefore, we conclude that NTs in tendons could have a twofold function: long-distance communication as well as stabilization of a mechanically challenged tissue. From in vitro studies it is known that NTs allow intercellular transmission of various cell components, offering potential protective effects for the respective tissue. Further studies on functional properties of NTs in tendons under changing mechanical loading regimens are required in the future. The fact that NTs are present in tendons may necessitate the reconsideration of our traditional understanding of cell-to-cell communication.

Dataset Information

C3: connect separate connected components to form a succinct disease module.

Background

Results

Conclusions

Publications

C3: connect separate connected components to form a succinct disease module.

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