Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes.
We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Feng
F
Miao
Zhuo
Z
Chen
Saul
S
Genuth
Andrew
A
Paterson
Lingxiao
L
Zhang
Xiwei
X
Wu
Sierra Min
SM
Li
Patricia
P
Cleary
Arthur
A
Riggs
David M
DM
Harlan
Gayle
G
Lorenzi
Orville
O
Kolterman
Wanjie
W
Sun
John M
JM
Lachin
Rama
R
Natarajan
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged
D001786:Blood Glucose; D006657:Histones; D007004:Hypoglycemic Agents