Epigenetics in diabetic nephropathy, immunity and metabolism
Epigenetics in diabetic nephropathy, immunity and metabolism
Samuel T. Keating 0 1 2 3
Janna A. van Diepen 0 1 2 3
Niels P. Riksen 0 1 2 3
Assam El-Osta 0 1 2 3
Samuel T. Keating 0 1 2 3
0 Department of Pathology, The University of Melbourne , Parkville, VIC , Australia
1 Central Clinical School, Monash University , 99 Commercial Road, Melbourne, VIC 3004 , Australia
2 Department of Internal Medicine, Department of Internal Medicine (463), Radboud University Medical Center , Nijmegen, PO Box 9101, 6500 HB Nijmegen , the Netherlands
3 Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong , Hong Kong, SAR , China
When it comes to the epigenome, there is a fine line between clarity and confusion-walk that line and you will discover another fascinating level of transcription control. With the genetic code representing the cornerstone of rules for information that is encoded to proteins somewhere above the genome level there is a set of rules by which chemical information is also read. These epigenetic modifications show a different side of the genetic code that is diverse and regulated, hence modifying genetic transcription transiently, ranging from short- to long-term alterations. While this complexity brings exquisite control it also poses a formidable challenge to efforts to decode mechanisms underlying complex disease. Recent technological and computational advances have improved unbiased acquisition of epigenomic patterns to improve our understanding of the complex chromatin landscape. Key to resolving distinct chromatin signatures of diabetic complications is the identification of the true physiological targets of regulatory proteins, such as reader proteins that recognise, writer proteins that deposit and eraser proteins that remove specific chemical moieties. But how might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective? Drawing from an ever-expanding compendium of experimental and clinical studies, this review details the current state-of-play and provides a perspective of chromatin-dependent mechanisms implicated in diabetic complications, with a special focus on diabetic nephropathy. We hypothesise a codified signature of the diabetic epigenome and provide examples of prime candidates for chemical modification. As for the pharmacological control of epigenetic marks, we explore future strategies to expedite and refine the search for clinically relevant discoveries. We also consider the challenges associated with therapeutic strategies targeting epigenetic pathways.
Chromatin; Diabetes; Diabetic complications; Diabetic nephropathy; Epigenetics; EWAS; Histone; Innate immune memory; Vascular
Abbreviations
5hmC 5-Hydroxymethylcytosine
5mC 5-Methylcytosine
BCG Bacillus Calmette–Guérin vaccine
CpG Cytosine–guanine dinucleotide
CTCF CCCTC-binding factor
DCCT Diabetes Control and Complications Trial
DNMT DNA methyltransferase
EDIC Epidemiology of Diabetes Interventions and
Complications
ESRD End-stage renal disease
EZH2 Enhancer of zeste 2 repressive complex 2 subunit
Introduction
Vascular disease affecting nearly all types of blood vessels is
common to both type 1 and type 2 diabetes mellitus.
Accelerated rates of clinically defined macrovascular
complications, such as myocardial infarction and stroke, which result
from large vessel atherosclerosis remain the leading causes of
morbidity and premature mortality in the diabetic population.
Diabetes is also associated with the occurrence of adverse
microvascular complications, manifesting clinically as
retinopathy, neuropathy and nephropathy.
Extensive debate surrounds the extent to which diabetic
microvascular and macrovascular complications represent a
continuous pathological spectrum. Closely related to this
debate is the question of why not all people with diabetes
complications experience more advanced forms of vascular
disease. Though yet to be completely defined mechanistically,
t h e p e r s i s t e n t a n d h a r m f u l e f f e c t s o f a n t e c e d e n t
hyperglycaemia may at least partly explain the variation in
vascular deterioration. Nonetheless, the fundamental reasons
why a proportion of diabetic individuals appear to be
protected from serious complications remain poorly
understood. Despite the promises of the genetic revolution,
contemporary knowledge of the impact of genetic variation on
diabetes does not adequately explain the disproportionate
distribution and severity of diabetic vascular complications.
Realisation of novel preventative and therapeutic
approaches hinges on improved characterisation of the
molecular events and interactions that underlie the development and
progression of diabetic vasculopathology. Interestingly,
however, some in the field have shifted their research focus to
understanding the post-translational and covalent chemical
chromatin modifications that contribute to transcriptional
regulation via structura (...truncated)