The Contribution of Histone Crotonylation to Tissue Health and Disease: Focus on Kidney Health

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are the most severe consequences of kidney injury. They are interconnected syndromes as CKD predisposes to AKI and AKI may accelerate CKD progression. Despite their growing impact on the global burden of disease, there is no satisfactory treatment for AKI and current therapeutic approaches to CKD remain suboptimal. Recent research has focused on the therapeutic target potential of epigenetic regulation of gene expression, including non-coding RNAs and the covalent modifications of histones and DNA. Indeed, several drugs targeting histone modifications are in clinical use or undergoing clinical trials. Acyllysine histone modifications (e.g. methylation, acetylation, and crotonylation) have modulated experimental kidney injury. Most recently, increased histone lysine crotonylation (Kcr) was observed during experimental AKI and could be reproduced in cultured tubular cells exposed to inflammatory stress triggered by the cytokine TWEAK. The degree of kidney histone crotonylation was modulated by crotonate availability and crotonate supplementation protected from nephrotoxic AKI. We now review the functional relevance of histone crotonylation in kidney disease and other pathophysiological contexts, as well as the implications for the development of novel therapeutic approaches. These studies provide insights into the overall role of histone crotonylation in health and disease.

Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

“… 78 Most recently, the protective part of HDAC inhibitors in kidney diseases may be related to their role in crotonylation regulation, which could promote some nephroprotective genes, such as PGC1α and Sirt-3. 79 This opens the door to explore therapeutic strategies based on the modulation of histone crotonylation.…”

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

“…HDACs, and more specifically class I HDACs, also have decrotonylase activity, although Kcr is more resistant to deacylation than Kac, supporting the idea of a robust transcription [40,41]. Kcr is also regulated by metabolic pathways that control crotonate availability [42]. Crotonate is the short-chain fatty acid precursor of crotonyl-CoA, a chemical process catalyzed by the Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) [38].…”

“…Crotonate is the short-chain fatty acid precursor of crotonyl-CoA, a chemical process catalyzed by the Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) [38]. In cultured kidney cells, crotonate availability was associated with increased or decreased gene expression of genes involved in the pathogenesis of kidney disease [42,43].…”

“…Constitutive histone crotonylation is present in different healthy tissues, including the kidney [20], and increased histone crotonylation has been described during experimental nephrotoxic AKI [43] (Table 3) suggesting a role of histone crotonylation in kidney injury, although there are not yet any studies in DKD [42]. In this regard, modulation of the levels of histone crotonylation modifies the outcome of kidney injury [43].…”

Global Lysine Crotonylation Profiling of Mouse Liver

“…[4][5][6] Several biological processes, including kidney diseases, HIV latency, depression, and telomere rejuvenation, have since been associated with crotonylation, however, mechanistic studies have focused primarily on histones. [7][8][9][10][11] Kcr in non-histone proteins was originally identified in HeLa, A549, and H1299 cell lines, [12][13][14] and a recent crotonylome dataset established in HeLa cells identified 14 311 Kcr sites across 3734 proteins. [15] Some reports have also shown the presence of crotonylation in zebrafish, papaya, and rice.…”