Predictive network modeling in human induced pluripotent stem cells identifies key driver genes for insulin responsiveness.
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
10
12
2019
accepted:
03
11
2020
revised:
07
01
2021
pubmed:
29
12
2020
medline:
20
2
2021
entrez:
28
12
2020
Statut:
epublish
Résumé
Insulin resistance (IR) precedes the development of type 2 diabetes (T2D) and increases cardiovascular disease risk. Although genome wide association studies (GWAS) have uncovered new loci associated with T2D, their contribution to explain the mechanisms leading to decreased insulin sensitivity has been very limited. Thus, new approaches are necessary to explore the genetic architecture of insulin resistance. To that end, we generated an iPSC library across the spectrum of insulin sensitivity in humans. RNA-seq based analysis of 310 induced pluripotent stem cell (iPSC) clones derived from 100 individuals allowed us to identify differentially expressed genes between insulin resistant and sensitive iPSC lines. Analysis of the co-expression architecture uncovered several insulin sensitivity-relevant gene sub-networks, and predictive network modeling identified a set of key driver genes that regulate these co-expression modules. Functional validation in human adipocytes and skeletal muscle cells (SKMCs) confirmed the relevance of the key driver candidate genes for insulin responsiveness.
Identifiants
pubmed: 33362275
doi: 10.1371/journal.pcbi.1008491
pii: PCOMPBIOL-D-19-02146
pmc: PMC7790417
doi:
Substances chimiques
Insulin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008491Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK106236
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120565
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107437
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG009649
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116750
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL107388
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057457
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116074
Pays : United States
Déclaration de conflit d'intérêts
I have read the journal's policy and the authors of this manuscript have the following competing interests: RC is the founder of INTelico Therapeutics LLC.
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