The epigenetic mechanisms regulating adipose tissue development and function are poorly understood. In this study, we show that depletion of histone H3K36 methylation by H3.3K36M in preadipocytes inhibits adipogenesis by increasing H3K27me3 to prevent the induction of C/EBPα and other targets of the master adipogenic transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). Depleting H3K36 methyltransferase Nsd2, but not Nsd1 or Setd2, phenocopies the effects of H3.3K36M on adipogenesis and PPARγ target expression. Consistently, expression of H3.3K36M in progenitor cells impairs brown adipose tissue (BAT) and muscle development in mice. In contrast, depletion of histone H3K36 methylation by H3.3K36M in adipocytes in vivo does not affect adipose tissue weight, but leads to profound whitening of BAT and insulin resistance in white adipose tissue (WAT). These mice are resistant to high fat diet-induced WAT expansion and show severe lipodystrophy. Together, these results suggest a critical role of Nsd2-mediated H3K36 methylation in adipose tissue development and function.

BACKGROUND: Pathological cardiac remodeling after myocardial infarction (MI) is a leading cause of heart failure and sudden death. The detailed mechanisms underlying the transition to heart failure after MI are not fully understood. Disruptions in the endoplasmic reticulum (ER)–mitochondria connectivity, along with mitochondrial dysfunction, are substantial contributors to this remodeling process. In this study, we aimed to explore the impact of mitochondrial tumor suppressor 1A (Mtus1A) on cardiac remodeling subsequent to MI and elucidate its regulatory role in ER-mitochondria interactions. METHODS: Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of mitochondrial tumor suppressor 1 (Mtus1) in human cardiomyocytes under ischemic stress. MI models were induced in mice by left coronary artery ligation and replicated in vitro using primary neonatal rat ventricular myocytes exposed to oxygen glucose deprivation. Cardiac-specific deletion of Mtus1 was achieved by crossing floxed Mtus1 mice with the Myh6-MerCreMer mice. The impact of Mtus1A, a mitochondrial isoform of Mtus1, on cardiac function and the molecular mechanisms were investigated in both in vivo and in vitro settings. Mitochondria-associated ER membranes (MAMs) coupling levels were evaluated by transmission electron microscopy and live-cell imaging. Protein interactions involving Mtus1A were explored through immunoprecipitation–mass spectrometry, coimmunoprecipitation, and proximity ligation assay. The roles of Mtus1A and Fbxo7 (F-box protein 7) were validated in a murine MI model using adeno-associated virus serotype 9 (AAV9). RESULTS: Bioinformatics analysis revealed a significant downregulation of Mtus1 expression in human cardiomyocytes under ischemic conditions, indicating its potential role in stress response. The predominant isoform in murine cardiomyocytes, Mtus1A, showed reduced expression in the left ventricle of mice after MI, which is consistent with the decreased levels of its orthologs in heart tissues from patients with MI. Cardiac-specific Mtus1-knockout mice exhibited worsened cardiac dysfunction after MI. Further studies demonstrated that Mtus1A partially localizes to MAMs, where it modulates MAMs coupling and preserves mitochondrial function. Mechanistically, Mtus1A functions as a scaffold protein that maintains the formation of inositol 1,4,5-trisphosphate receptor 1 (IP ₃ R1)–glucose-regulated protein 75 (Grp75)–voltage-dependent anion channel 1 (VDAC1) complex through its amino acid sequence 189-219. In addition, Mtus1A protein is stabilized by K6-linked ubiquitination through the E3 ubiquitin ligase Fbxo7. Mtus1A overexpression in mice mitigated MI-induced cardiac dysfunction and remodeling by maintaining MAMs integrity. CONCLUSIONS: Our study demonstrates that Mtus1A is crucial for modulating MI-induced cardiac remodeling by preserving ER-mitochondria communication and ameliorating mitochondrial function in cardiomyocytes. Mtus1A may serve as a potential therapeutic target for treating heart failure after MI.

Pulmonary arterial hypertension (PAH) is a rare cardiovascular disease with very high mortality rate. The currently available therapeutic strategies, which improve symptoms, cannot fundamentally reverse the condition. Thus, new therapeutic strategies need to be established. Our research analyzed three microarray datasets of lung tissues from human PAH samples retrieved from the Gene Expression Omnibus (GEO) database. We combined two datasets for subsequent analyses, with the batch effects removed. In the merged dataset, 542 DEGs were identified and the key module relevant to PAH was selected using WGCNA. GO and KEGG analyses of DEGs and the key module indicated that the pre-ribosome, ribosome biogenesis, centriole, ATPase activity, helicase activity, hypertrophic cardiomyopathy, melanoma, and dilated cardiomyopathy pathways are involved in PAH. With the filtering standard (|MM| > 0.95 and |GS| > 0.90), 70 hub genes were identified. Subsequently, five candidate marker genes (CDC5L, AP3B1, ZFYVE16, DDX46, and PHAX) in the key module were found through overlapping with the top thirty genes calculated by two different methods in CytoHubb. Two of them (CDC5L and DDX46) were found to be significantly upregulated both in the merged dataset and the validating dataset in PAH patients. Meanwhile, expression of the selected genes in lung from PAH chicken measured by qRT-PCR and the ROC curve analyses further verified the potential marker genes’ predictive value for PAH. In conclusion, CDC5L and DDX46 may be marker genes and potential therapeutic targets for PAH.

Background: Considered as one of the major reasons of sudden cardiac death, hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease. However, effective treatment for HCM is still lacking. Identification of hub gene may be a powerful tool for discovering potential therapeutic targets and candidate biomarkers. Methods: We analysed three gene expression datasets for HCM from the Gene Expression Omnibus. Two of them were merged by “sva” package. The merged dataset was used for analysis while the other dataset was used for validation. Following this, a weighted gene coexpression network analysis (WGCNA) was performed, and the key module most related to HCM was identified. Based on the intramodular connectivity, we identified the potential hub genes. Then, a receiver operating characteristic curve analysis was performed to verify the diagnostic values of hub genes. Finally, we validated changes of hub genes, for genetic transcription and protein expression levels, in datasets of HCM patients and myocardium of transverse aortic constriction (TAC) mice. Results: In the merged dataset, a total of 455 differentially expressed genes (DEGs) were identified from normal and hypertrophic myocardium. In WGCNA, the blue module was identified as the key module and the genes in this module showed a high positive correlation with HCM. Functional enrichment analysis of DEGs and key module revealed that the extracellular matrix, fibrosis, and neurohormone pathways played important roles in HCM. FRZB, COL14A1, CRISPLD1, LUM, and sFRP4 were identified as hub genes in the key module. These genes showed a good predictive value for HCM and were significantly up-regulated in HCM patients and TAC mice. We also found protein expression of LUM and sFRP4 increased in myocardium of TAC mice. Conclusion: This study revealed that five hub genes are involved in the occurrence and development of HCM, and they are potentially to be used as therapeutic targets and biomarkers for HCM.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high morbidity and mortality. Existing evidence suggests that the central pathogenesis to aHUS might be endothelial cell damage. Nevertheless, the role of endothelial cell alterations in aHUS has not been well characterized and the underlying mechanisms remain unclear. Utilizing an induced pluripotent stem cell-derived endothelial cell (iPSC-EC) model, we showed that anti-complement factor H autoantibody-associated aHUS patient-specific iPSC-ECs exhibited an intrinsic defect in endothelial functions. Stimulation using aHUS serums exacerbated endothelial dysfunctions, leading to cell apoptosis in iPSC-ECs. Importantly, we identified p38 as a novel signaling pathway contributing to endothelial dysfunctions in aHUS. These results illustrate that iPSC-ECs can be a reliable model to recapitulate EC pathological features, thus providing a unique platform for gaining mechanistic insights into EC injury in aHUS. Our findings highlight that the p38 MAPK signaling pathway can be a therapeutic target for treatment of aHUS.