Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0018801 (
heart failure
)
72,216
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Methyltransferases are a superfamily of enzymes that transfer methyl groups to proteins, nucleic acids, and small molecules. Traditionally, these enzymes have been shown to carry out a specific modification (mono-, di-, or trimethylation) on a single, or limited number of, amino acid(s). The largest subgroup of this family, protein methyltransferases, target arginine and
lysine
side chains of histone molecules to regulate gene expression. Although there is a large number of functional studies that have been performed on individual methyltransferases describing their methylation targets and effects on biological processes, no analyses exist describing the spatial distribution across tissues or their differential expression in the diseased heart. For this review, we performed tissue profiling in protein databases of 199 confirmed or putative methyltransferases to demonstrate the unique tissue-specific expression of these individual proteins. In addition, we examined transcript data sets from human
heart failure
patients and murine models of heart disease to identify 40 methyltransferases in humans and 15 in mice, which are differentially regulated in the heart, although many have never been functionally interrogated. Lastly, we focused our analysis on the largest subgroup, that of protein methyltransferases, and present a newly emerging phenomenon in which 16 of these enzymes have been shown to play dual roles in regulating transcription by maintaining the ability to both activate and repress transcription through methyltransferase-dependent or -independent mechanisms. Overall, this review highlights a novel paradigm shift in our understanding of the function of histone methyltransferases and correlates their expression in heart disease.
...
PMID:Transcriptional regulation by methyltransferases and their role in the heart: highlighting novel emerging functionality. 3282 44
Altered redox biology and oxidative stress have been implicated in the progression of
heart failure
. Glutaredoxin-2 (GRX2) is a glutathione-dependent oxidoreductase and catalyzes the reversible deglutathionylation of mitochondrial proteins. Sirtuin-3 (SIRT3) is a class III histone deacetylase and regulates
lysine
acetylation in mitochondria. Both GRX2 and SIRT3 are considered as key in the protection against oxidative damage in the myocardium. Knockout of either contributes to adverse heart pathologies including hypertrophy, hypertension, and cardiac dysfunction. Here, we created and characterized a GRX2 and SIRT3 double-knockout mouse model, hypothesizing that their deletions would have an additive effect on oxidative stress, and exacerbate mitochondrial function and myocardial structural remodeling. Wildtype, single-gene knockout (Sirt3
-/-
, Grx2
-/-
), and double-knockout mice (Grx2
-/-
/Sirt3
-/-
) were compared in heart weight, histology, mitochondrial respiration and H
2
O
2
production. Overall, the hearts from Grx2
-/-
/Sirt3
-/-
mice displayed increased fibrosis and hypertrophy versus wildtype. In the Grx2
-/-
and the Sirt3
-/-
we observed changes in mitochondrial oxidative capacity, however this was associated with elevated H
2
O
2
emission only in the Sirt3
-/-
. Similar changes were observed but not worsened in hearts from Grx2
-/-
/Sirt3
-/-
mice, suggesting that these changes were not additive. In human myocardium, using genetic and histopathological data from the human Genotype-Tissue Expression consortium, we confirmed that SIRT3 expression correlates inversely with heart pathology. Altogether, GRX2 and SIRT3 are important in the control of cardiac mitochondrial redox and oxidative processes, but their combined absence does not exacerbate effects, consistent with the overall conclusion that they function together in the complex redox and antioxidant systems in the heart.
...
PMID:Glutaredoxin-2 and Sirtuin-3 deficiencies impair cardiac mitochondrial energetics but their effects are not additive. 3300 79
Background:
Gene regulatory networks control tissue homeostasis and disease progression in a cell-type specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue-specificity of their function is achieved are poorly understood. BRD4, a member of the BET (Bromo- and Extra-Terminal domain) family of ubiquitously expressed acetyl-
lysine
reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease, and has been implicated as a pharmacologic target in
heart failure
. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown.
Methods:
We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classical molecular biology and biochemical approaches to understand the role of BRD4 in adult cardiomyocyte homeostasis.
Results:
Here, we show that cardiomyocyte-specific deletion of
Brd4
in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature enriched for decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master co-activators
Ppargc1a
,
Ppargc1b
, and their downstream targets) and preferentially co-localizes with GATA4, a lineage determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomainindependent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity.
Conclusions:
These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte specific gene program governing bioenergetic homeostasis in the adult heart.
...
PMID:BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes. 3309 44
<< Previous
1
2
3
4
5
6
7
8
9
