DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes.

Nature Metabolism
Zhuo ChenRama Natarajan

Abstract

Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine-guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that...Continue Reading

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Citations

Jan 21, 2021·Nutrients·Ran NakamichiHiroshi Itoh
Mar 5, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Robin P ChoudhuryEdward A Fisher
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Jul 3, 2021·The Journal of Clinical Endocrinology and Metabolism·Hakyung KimSoo Heon Kwak
Oct 12, 2021·Frontiers in Pharmacology·Erina SugitaHiroshi Itoh

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Datasets Mentioned

BETA
GSE76169
GSE75170
EDIC499
EDIC61
GSE56046

Methods Mentioned

BETA
amplicon sequencing
amplicon-seq
blood collection
Hi-C
genotyping
blood draw
amplicon-seqs
ChIP-seq

Software Mentioned

circlize ’
seqLogo
R Bioconductor package ‘ Minfi ’
qqman ’
Minfi
TwoSampleMR
ggplot2
Bioconductor R package
R package ‘ survival ’
gplots ’

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