Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function
Developmental defects in motile cilia, arising from genetic abnormalities in one or more ciliary genes, can lead to a common ciliopathy known as primary ciliary dyskinesia (PCD). Functional studies in model organisms undertaken to understand PCD or cilia biogenesis have identified 100s of genes regu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00023/full |
| _version_ | 1818493293979238400 |
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| author | Ishita Mukherjee Sudipto Roy Sudipto Roy Sudipto Roy Saikat Chakrabarti |
| author_facet | Ishita Mukherjee Sudipto Roy Sudipto Roy Sudipto Roy Saikat Chakrabarti |
| author_sort | Ishita Mukherjee |
| collection | DOAJ |
| description | Developmental defects in motile cilia, arising from genetic abnormalities in one or more ciliary genes, can lead to a common ciliopathy known as primary ciliary dyskinesia (PCD). Functional studies in model organisms undertaken to understand PCD or cilia biogenesis have identified 100s of genes regulated by Foxj1, the master regulator of motile ciliogenesis. However, limited systems based studies have been performed to elucidate proteins or network/s crucial to the motile ciliary interactome, although this approach holds promise for identification of multiple cilia-associated genes, which, in turn, could be utilized for screening and early diagnosis of the disease. Here, based on the assumption that FOXJ1-mediated regulatory and signaling networks are representative of the motile cilia interactome, we have constructed and analyzed the gene regulatory and protein–protein interaction network (PPIN) mediated by FOXJ1. The predicted FOXJ1 regulatory network comprises of 424 directly and 148 indirectly regulated genes. Additionally, based on gene ontology analysis, we have associated 17 directly and 6 indirectly regulated genes with possible ciliary roles. Topological and perturbation analyses of the PPIN (6927 proteins, 40,608 interactions) identified 121 proteins expressed in ciliated cells, which interact with multiple proteins encoded by FoxJ1 induced genes (FIG) as important interacting proteins (IIP). However, it is plausible that IIP transcriptionally regulated by FOXJ1 and/or differentially expressed in PCD are likely to have crucial roles in motile cilia. We have found 20 de-regulated topologically important effector proteins in the FOXJ1 regulatory network, among which some (PLSCR1, SSX2IP, ACTN2, CDC42, HSP90AA1, PIAS4) have previously reported ciliary roles. Furthermore, based on pathway enrichment of these proteins and their primary interactors, we have rationalized their possible roles in the ciliary interactome. For instance, 5 among these novel proteins that are involved in cilia associated signaling pathways (like Notch, Wnt, Hedgehog, Toll-like receptor etc.) could be ‘topologically important signaling proteins.’ Therefore, based on this FOXJ1 network study we have predicted important effectors in the motile cilia interactome, which are possibly associated with ciliary biology and/or function and are likely to further our understanding of the pathophysiology in ciliopathies like PCD. |
| first_indexed | 2024-12-10T17:52:59Z |
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| id | doaj.art-0c950166db414b3aa7c6e1a3c8994ff5 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-10T17:52:59Z |
| publishDate | 2019-03-01 |
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| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-0c950166db414b3aa7c6e1a3c8994ff52022-12-22T01:39:00ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-03-011010.3389/fgene.2019.00023416138Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary FunctionIshita Mukherjee0Sudipto Roy1Sudipto Roy2Sudipto Roy3Saikat Chakrabarti4Translational Research Unit of Excellence, Structural Biology and Bioinformatics Division, Council for Scientific and Industrial Research – Indian Institute of Chemical Biology, Kolkata, IndiaInstitute of Molecular and Cell Biology, Singapore, SingaporeDepartment of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Biological Sciences, National University of Singapore, Singapore, SingaporeTranslational Research Unit of Excellence, Structural Biology and Bioinformatics Division, Council for Scientific and Industrial Research – Indian Institute of Chemical Biology, Kolkata, IndiaDevelopmental defects in motile cilia, arising from genetic abnormalities in one or more ciliary genes, can lead to a common ciliopathy known as primary ciliary dyskinesia (PCD). Functional studies in model organisms undertaken to understand PCD or cilia biogenesis have identified 100s of genes regulated by Foxj1, the master regulator of motile ciliogenesis. However, limited systems based studies have been performed to elucidate proteins or network/s crucial to the motile ciliary interactome, although this approach holds promise for identification of multiple cilia-associated genes, which, in turn, could be utilized for screening and early diagnosis of the disease. Here, based on the assumption that FOXJ1-mediated regulatory and signaling networks are representative of the motile cilia interactome, we have constructed and analyzed the gene regulatory and protein–protein interaction network (PPIN) mediated by FOXJ1. The predicted FOXJ1 regulatory network comprises of 424 directly and 148 indirectly regulated genes. Additionally, based on gene ontology analysis, we have associated 17 directly and 6 indirectly regulated genes with possible ciliary roles. Topological and perturbation analyses of the PPIN (6927 proteins, 40,608 interactions) identified 121 proteins expressed in ciliated cells, which interact with multiple proteins encoded by FoxJ1 induced genes (FIG) as important interacting proteins (IIP). However, it is plausible that IIP transcriptionally regulated by FOXJ1 and/or differentially expressed in PCD are likely to have crucial roles in motile cilia. We have found 20 de-regulated topologically important effector proteins in the FOXJ1 regulatory network, among which some (PLSCR1, SSX2IP, ACTN2, CDC42, HSP90AA1, PIAS4) have previously reported ciliary roles. Furthermore, based on pathway enrichment of these proteins and their primary interactors, we have rationalized their possible roles in the ciliary interactome. For instance, 5 among these novel proteins that are involved in cilia associated signaling pathways (like Notch, Wnt, Hedgehog, Toll-like receptor etc.) could be ‘topologically important signaling proteins.’ Therefore, based on this FOXJ1 network study we have predicted important effectors in the motile cilia interactome, which are possibly associated with ciliary biology and/or function and are likely to further our understanding of the pathophysiology in ciliopathies like PCD.https://www.frontiersin.org/article/10.3389/fgene.2019.00023/fullFOXJ1motile ciliaprimary ciliary dyskinesiaciliopathytranscriptional networkprotein–protein interaction |
| spellingShingle | Ishita Mukherjee Sudipto Roy Sudipto Roy Sudipto Roy Saikat Chakrabarti Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function Frontiers in Genetics FOXJ1 motile cilia primary ciliary dyskinesia ciliopathy transcriptional network protein–protein interaction |
| title | Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function |
| title_full | Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function |
| title_fullStr | Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function |
| title_full_unstemmed | Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function |
| title_short | Identification of Important Effector Proteins in the FOXJ1 Transcriptional Network Associated With Ciliogenesis and Ciliary Function |
| title_sort | identification of important effector proteins in the foxj1 transcriptional network associated with ciliogenesis and ciliary function |
| topic | FOXJ1 motile cilia primary ciliary dyskinesia ciliopathy transcriptional network protein–protein interaction |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00023/full |
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