KDM5B

Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates the phenotypic transition of macrophages; however, the precise mechanisms governing metabolic reprogramming of cardiac reparative macrophages remain poorly understood. In this study, we investigated the role of NPM1 (nucleophosmin 1) in the metabolic and phenotypic shift of cardiac macrophages in the context of MI and explored the therapeutic effect of targeting NPM1 for ischemic tissue repair.

Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI to explore NPM1 expression and its correlation with prognostic indicators. Through RNA sequencing, metabolite profiling, histology, and phenotype analyses, we investigated the role of NPM1 in postinfarct cardiac repair using macrophage-specific NPM1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and phenotype transition of NPM1-deficient cardiac macrophages. The therapeutic efficacy of antisense oligonucleotide and inhibitor targeting NPM1 was then assessed in wild-type mice with MI.

NPM1 expression was upregulated in the peripheral blood mononuclear cells from patients with MI that closely correlated with adverse prognostic indicators of MI. Macrophage-specific NPM1 deletion reduced infarct size, promoted angiogenesis, and suppressed tissue fibrosis, in turn improving cardiac function and protecting against adverse cardiac remodeling after MI. Furthermore, NPM1 deficiency boosted the reparative function of cardiac macrophages by shifting macrophage metabolism from the inflammatory glycolytic system to oxygen-driven mitochondrial energy production., The oligomeric NPM1 mechanistically recruited histone demethylase KDM5b to the promoter of Tsc1 (TSC complex subunit 1), the mTOR (mechanistic target of rapamycin kinase) complex inhibitor, reduced histone H3K4me3 modification, and inhibited TSC1 expression, which then facilitated mTOR-related inflammatory glycolysis and antagonized the reparative function of cardiac macrophages. The in vivo administration of antisense oligonucleotide targeting NPM1 or oligomerization inhibitor NSC348884 substantially ameliorated tissue injury and enhanced cardiac recovery in mice after MI.

Our findings uncover the key role of epigenetic factor NPM1 in impeding postinfarction cardiac repair by remodeling metabolism pattern and impairing the reparative function of cardiac macrophages. NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for heart failure after MI.

Metastasis determines clinical management decision and restricts the therapeutic efficiency in patients with squamous cell carcinoma of the head and neck (SCCHN). Epigenetic factor KDM5B serves as an oncogene in multiple cancers. However, its role in SCCHN metastasis remains unclear. Our previous study showed that KDM5B is significantly elevated in SCCHN tissue and is positively correlated with metastasis and recurrence. KDM5B overexpression predicted a poor prognosis in both disease-free survival and overall survival, which served as an independent prognostic factor in SCCHN patients. This study further investigates the exact impact of KDM5B in metastasis of SCCHN. We found that KDM5B knockdown significantly inhibits the migration and invasion of SCCHN cells both in vitro and in vivo. On the contrary, forced expression of KDM5B leads to enhanced migration and invasion, accompanied by canonical alterations of epithelial-mesenchymal transition (EMT). Mechanism investigations demonstrated that KDM5B activates Wnt/β-catenin pathway, and inhibition of Wnt/β-catenin pathway via a small molecule inhibitor iCRT-14 partially reverses the enhanced migratory and invasive ability caused by KDM5B in SCCHN cells. Together, our data indicate that KDM5B promotes EMT and metastasis via Wnt/β-catenin pathway in SCCHN, suggesting that KDM5B may be a potential therapeutic target and prognosis biomarker in SCCHN.

Cardiac arrhythmias are a common health problem. Both common and rare genetic risk factors exist for cardiac arrhythmias. Cardiac amyloidosis is a rare disease that may manifest various arrhythmias. Few large-scale whole exome sequencing studies elucidating the contribution of rare variations to arrhythmias have been published.

To access gene collapsing analysis of rare variations for different types of cardiac arrhythmias in UK Biobank. Identified genes were analyzed in silico for probability to form amyloid fibrils.

We used 2 published UK Biobank portals (https://azphewas.com/ and https://app.genebass.org/) to access gene collapsing analysis of rare variations for different types of cardiac arrhythmias. Diagnosis of arrhythmia was based on the International Classification of Diseases, 10th Revision (ICD-10) codes: conduction disorders (I44, I45), paroxysmal tachycardia (I47), atrial fibrillation (I48), and other arrhythmias (I49).

Rare variations in 5 genes were linked to conduction disorders (SCN5A, LMNA, SMAD6, HSPB9, TMEM95). The TTN gene was associated with both paroxysmal tachycardia and other arrhythmias. Atrial fibrillation was associated with rare variations in 8 genes (TTN, RPL3L, KLF1, TET2, NME3, KDM5B, PKP2, PMVK). Two of the genes linked to heart conduction disorders were potential amyloid-forming proteins (HSPB9, TMEM95), while none of the 8 genes linked to other types of arrhythmias were potential amyloid-forming proteins.

Rare variations in 13 genes were associated with arrhythmias in the UK Biobank. Two of the heart conduction disorder-linked genes are potential amyloid-forming candidates. Amyloid formation may be an underestimated cause of heart conduction disorders.