Preserved DNA Damage Checkpoint Pathway Protects From Complications in Long-standing Type 1 Diabetes

ABSTRACT: Gene expression analyses of fibroblasts obtained from healthy controls, Medalist -C patients and Medalist +C patients. Type 1diabetes (T1D) is associated with late complications, mechanisms underscoring which are poorly understood. We report the derivation of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50years) with severe (designated Medalist +C) or absent to mild complications (designated Medalist -C). Disease modeling of iPSCs revealed impairment in growth, reprogramming and differentiation in Medalist +C. Further investigations using genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist –C. In silico analyses revealed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs showed enhanced susceptibility to genotoxic stress that worsened upon miR200 over-expression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage response. In summary, we report miR200 regulated DNA damage checkpoint pathway as a potential target for therapeutic intervention for treating complications of diabetes. Clinical Characteristics of 50 year Medalist Type 1 Diabetes (T1D) patients Medalist –C: 0/6 with CVD, 5/6 have DN Class 0-IIA, and 6/6 have no to mild NPDR. Medalist +C: 6/6 with CVD, 5/6 have DN Class IIB or IV, and 4/6 have PDR. CVD: cardiovascular disease; DN class: diabetic nephropathy class, PDR: proliferative diabetic retinopathy; NPDR: non proliferative diabetic retinopathy

ORGANISM(S): Homo sapiens

PROVIDER: GSE70752 | GEO | 2015/08/15

SECONDARY ACCESSION(S): PRJNA289501

REPOSITORIES: GEO