NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model.

Nature Communications
Jennifer M PetersonDenis C Guttridge

Abstract

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-κB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function.

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Citations

Apr 6, 2019·Journal of Cellular and Molecular Medicine·Kaowen YanPeifeng Li
Feb 13, 2019·Life Science Alliance·Christopher R HeierChristopher F Spurney
Jul 14, 2020·Frontiers in Bioengineering and Biotechnology·Sarka JelinkovaVladimir Rotrekl
Jan 6, 2021·International Journal of Molecular Sciences·Moises Rodriguez-GonzalezAna Castellano-Martinez
Nov 25, 2020·International Journal of Molecular Sciences·Mikhail V DubininKonstantin N Belosludtsev
Mar 19, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Bianca J J M BrundelDeli Zhang
Mar 17, 2020·Cell Calcium·Luigi FormisanoLucio Annunziato
Mar 6, 2021·Orphanet Journal of Rare Diseases·Stephanie KourakisEmma Rybalka
May 22, 2020·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Aristidis TsatsakisAntonio F Hernández
Apr 25, 2021·Seminars in Pediatric Neurology·Samuel J MackenzieJerry R Mendell

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Methods Mentioned

BETA
ubiquitination
ChIP
acetylation
ChIPs
ChIP-seq
Electrophoretic mobility shift assay
PCR

Software Mentioned

GraphPad
GraphPad Prism
HOMER ( Hypergeometric Optimization of Motif EnRichment )
Bowtie2
Java TreeView
Metascape
Cluster
Expression Console
Gene Set Enrichment Analysis
ChIPseeker

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