Abstract
Thalidomide is a known teratogen that causes malformations especially in heart and limbs. Its mechanism of teratogenicity is still not fully elucidated. Recently, a new target of thalidomide was described, TBX5, and was observed a new interaction between HAND2 and TBX5 that is disrupted in the presence of thalidomide. Therefore, our study aimed to raise potential candidates for thalidomide teratogenesis, through systems biology, evaluating HAND2 and TBX5 interaction and heart and limbs malformations of thalidomide. Genes and proteins related to TBX5 and HAND2 were selected through TF2DNA, REACTOME, Human Phenotype Ontology, and InterPro databases. Networks were assembled using STRING © database. Network analysis were performed in Cytoscape © and R v3.6.2. Differential gene expression (DGE) analysis was performed through gene expression omnibus. We constructed a network for HAND2 and TBX5 interaction; a network for heart and limbs malformations of TE; and the two joined networks. We observed that EP300 protein seemed to be important in all networks. We also looked for proteins containing C2H2 domain in the assembled networks. ZIC3, GLI1, GLI3, ZNF148, and PRDM16 were the ones present in both heart and limbs malformations of TE networks. Furthermore, in the DGE analysis after treatment with thalidomide, we observed that FANCB, ESCO2, and XRCC2 were downregulated and present both in heart and limbs networks. Through systems biology, we were able to point to different new proteins and genes, and selected specially EP300, which was important in all the analyzed networks, to be further evaluated in the TE teratogenicity.
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Acknowledgements
We acknowledge Têmis Maria Felix for helping and reviewing the phenotypes selected for cardiac and limbs malformations of TE.
Funding
This research was funded by Hospital de Clínicas de Porto Alegre (HCPA)—Fundo de Incentivo a Pesquisa e Eventos (FIPE), Grant numbers 2010-0244 and 2017-0248. FSLV is recipient of a Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) scholarship grant (Grant number CNPq 312993/2017-0). TWK was first recipient of a Coordination of Improvement of Higher Education Personnel (CAPES) scholarship (Grant 88881.132344/2016-01) and then of a CNPq scholarship (Grant 156158/2018-3). BDR is recipient of a CNPq scholarship (Grant 133335/2019-4).
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All authors contributed to the development of the idea and construction of the workflow of the analysis. BDR performed the analysis with help of TWK. BDR wrote the first draft of the manuscript. LSF reviewed the phenotypes selected for cardiac and limbs malformations of TE. TWK, FSLV and LRF contributed to the writing and rational of the analysis. All authors read and approved the final manuscript.
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Rengel, B.D., Schuler-Faccini, L., Fraga, L.R. et al. Possible New Candidates Involved to Thalidomide-Related Limbs and Cardiac Defects: A Systems Biology Approach. Biochem Genet 63, 2140–2160 (2025). https://doi.org/10.1007/s10528-024-10790-w
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DOI: https://doi.org/10.1007/s10528-024-10790-w