TY - JOUR
T1 - Network analysis reveals dysregulated functional patterns in type II diabetic skin
AU - Liu, Chunan
AU - Ram, Sudha
AU - Hurwitz, Bonnie L.
N1 - Funding Information:
Funding for this work was provided by the Gordon and Betty Moore Foundation [GBMF 8751 to B.L.H.].
Funding Information:
The authors thank the GTEx project for providing RNA-seq data. We thank Hurwitz Lab and Bio5 Institute, University of Arizona, for writing assistance, language editing, and funding support. We thank Dr. Alise Ponsero and Dr. Frank Duca for reviewing the manuscript and insightful discussion on the work.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Skin disorders are one of the most common complications of type II diabetes (T2DM). Long-term effects of high blood glucose leave individuals with T2DM more susceptible to cutaneous diseases, but its underlying molecular mechanisms are unclear. Network-based methods consider the complex interactions between genes which can complement the analysis of single genes in previous research. Here, we use network analysis and topological properties to systematically investigate dysregulated gene co-expression patterns in type II diabetic skin with skin samples from the Genotype-Tissue Expression database. Our final network consisted of 8812 genes from 73 subjects with T2DM and 147 non-T2DM subjects matched for age, sex, and race. Two gene modules significantly related to T2DM were functionally enriched in the pathway lipid metabolism, activated by PPARA and SREBF (SREBP). Transcription factors KLF10, KLF4, SP1, and microRNA-21 were predicted to be important regulators of gene expression in these modules. Intramodular analysis and betweenness centrality identified NCOA6 as the hub gene while KHSRP and SIN3B are key coordinators that influence molecular activities differently between T2DM and non-T2DM populations. We built a TF-miRNA-mRNA regulatory network to reveal the novel mechanism (miR-21-PPARA-NCOA6) of dysregulated keratinocyte proliferation, differentiation, and migration in diabetic skin, which may provide new insights into the susceptibility of skin disorders in T2DM patients. Hub genes and key coordinators may serve as therapeutic targets to improve diabetic skincare.
AB - Skin disorders are one of the most common complications of type II diabetes (T2DM). Long-term effects of high blood glucose leave individuals with T2DM more susceptible to cutaneous diseases, but its underlying molecular mechanisms are unclear. Network-based methods consider the complex interactions between genes which can complement the analysis of single genes in previous research. Here, we use network analysis and topological properties to systematically investigate dysregulated gene co-expression patterns in type II diabetic skin with skin samples from the Genotype-Tissue Expression database. Our final network consisted of 8812 genes from 73 subjects with T2DM and 147 non-T2DM subjects matched for age, sex, and race. Two gene modules significantly related to T2DM were functionally enriched in the pathway lipid metabolism, activated by PPARA and SREBF (SREBP). Transcription factors KLF10, KLF4, SP1, and microRNA-21 were predicted to be important regulators of gene expression in these modules. Intramodular analysis and betweenness centrality identified NCOA6 as the hub gene while KHSRP and SIN3B are key coordinators that influence molecular activities differently between T2DM and non-T2DM populations. We built a TF-miRNA-mRNA regulatory network to reveal the novel mechanism (miR-21-PPARA-NCOA6) of dysregulated keratinocyte proliferation, differentiation, and migration in diabetic skin, which may provide new insights into the susceptibility of skin disorders in T2DM patients. Hub genes and key coordinators may serve as therapeutic targets to improve diabetic skincare.
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U2 - 10.1038/s41598-022-10652-8
DO - 10.1038/s41598-022-10652-8
M3 - Article
C2 - 35477946
AN - SCOPUS:85128955233
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 6889
ER -