Citations

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function.

Abstract Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.

Introduction Mitral regurgitation (MR) is a common valvular disease associated with complications such as pulmonary hypertension, atrial fibrillation, and heart failure. However, its full impact on the cardiovascular system, especially on right heart function, is not yet fully understood. Understanding this relationship is important because the right ventricle (RV) is critical for maintaining cardiovascular function. Dysfunction of the RV, which may be contributed by conditions like MR, is strongly associated with poor clinical outcomes. Despite its importance, comprehensively studying MR's effect on the RV has been challenging due to the complex, interdependent nature of cardiovascular dynamics, limited patient data, and the difficulty in synthesizing disparate information to clarify the left heart-right heart connection. Methods The primary goal of this study is to investigate the effects of MR on cardiovascular hemodynamics and RV function by integrating 3D models of the left heart with a closed-loop 0D models of the entire cardiovascular system. We further conduct detailed analyses using patient-specific models to explore how various system modifications impact the RV, providing insights into the nuanced effects of MR on the right heart. Results and Discussion This analysis provides several clinically relevant insights. First, progressive MR markedly increases RV afterload and predisposes the RV to dysfunction, even when intrinsic RV contractility is preserved or enhanced. Second, MR-specific severity indices and left-heart metrics alone fail to capture the true burden on the right heart; RV impairment can progress despite stable or only modestly changing MR descriptors. Finally, these findings highlight the need to incorporate direct assessment of RV structure and function into the evaluation of MR, as RV vulnerability plays a critical role in determining patient risk and guiding management decisions.

Abstract Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 comutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and a higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants and our clinic-ready diagnostic workflow into the CMML diagnostic framework to improve accuracy. Significance: Through comprehensive clinical and genomic profiling of a large patient cohort, alongside immunophenotypic and transcriptional cellular analyses, this study provides evidence that incorporating genomic determinants into the diagnostic criteria for OM-CMML improves diagnostic accuracy and refines the identification of early-stage CMML, thereby preventing misclassification.

Introduction: Gastroesophageal reflux disease (GERD) plays an important role in lung transplant (LT) outcomes. This study aims to evaluate the impact of a novel sleep positioning device (SPD) on lung function in LT recipients with GERD. Methods: In this single-center cohort study, LT recipients (2014 to 2019) with GERD who were prescribed an SPD within 2 years of LT were included. A historical control group of LT recipients with GERD on PPI only (2011 to 2013) was selected to compare forced expiratory volume in 1 second (FEV1) as a marker of lung function. Results: Twenty LT recipients using SPD (cases) and 54 patients in the historical control group with proven GERD were included. Mean (SD) interval between LT and SPD prescription was 8.6 (5.7) months. Mean % predicted FEV1 was higher in SPD users than controls post-LT at 6 months (80% vs. 69%) and 1 year (80% vs. 71%), respectively. Among SPD users, post-SPD FEV1 was higher than pre-SPD FEV1 (82% vs. 70%). Conclusion: Use of a novel SPD can stabilize or improve pulmonary function in patients with GERD after LT. SPD may be a safe and cost-effective adjunctive therapy for the management of GERD after LT.

Sustained injury to renal tubular epithelial cells (TECs), driven by excessive autophagy, is a critical mechanism underlying kidney fibrosis. Our previous work identified JLP — a TEC-expressed scaffolding protein — as an endogenous antifibrotic factor that counteracts TGF-β1–induced autophagy and fibrogenesis. However, the mechanism underlying JLP downregulation in renal fibrosis remains unclear. Here, we delineated a TGF-β1/LEF1/β-catenin/JLP axis that governs TEC autophagy through a dichotomous regulatory circuit. Under physiological conditions, low levels of β-catenin and LEF1 with minimal nuclear localization permitted normal JLP expression, which in turn maintained autophagy in check. In contrast, during renal injury, TGF-β1 promoted the expression and nuclear translocation of β-catenin and LEF1, which together suppressed JLP transcription. This loss of JLP-mediated inhibition led to unchecked autophagy and exacerbated fibrotic damage. Analyses of kidney tissues from patients with CKD, murine fibrotic kidneys, and cultured HK-2 cells confirmed consistent JLP downregulation accompanied by upregulation and nuclear accumulation of LEF1 and β-catenin. Therapeutic intervention using the β-catenin/LEF1 inhibitor iCRT3 or LEF1-targeted silencing in murine fibrosis models restored JLP expression, attenuated TEC autophagy, and ameliorated renal fibrosis. These findings revealed an autoregulatory circuit controlling TEC autophagy and fibrogenesis, and supported LEF1 and β-catenin as potential therapeutic targets in CKD.

SUMMARY Artificial intelligence (AI)-based methods are increasingly critical in peptide drug discovery, but their applications are limited in a narrow scope such as antimicrobial peptides. For indications where peptide therapy inherently excels, such as metabolism, endocrinology, and tissue regeneration, AI-based pipeline for therapeutic peptide discovery is long awaited but still unmet. Here, we propose a deep learning-based pipeline, Deepeptide, capable of identifying therapeutic oligopeptides for various metabolism-related indications. Leveraging the intrinsical relationship of ‘disease indication — biological processes — molecular functions’, Deepeptide discovers oligopeptides with indication-ameliorating-related molecular functions as lead candidates for indication of interest. Deepeptide was applied in five representative indications of metabolism, endocrinology, and tissue regeneration: angiogenesis, lipid metabolism, osteogenesis, glucose metabolism, and anti-angiogenesis. Overall, 62% of the identified oligopeptide candidates demonstrated significant bioactivity in vitro, with most of them showing comparable potency to the first-line drugs. Notably, the heptapeptide AP7 exhibited angiogenic potency comparable to VEGF in excisional wound splinting mouse model by promoting cell migration rather than proliferation, and hexapeptide TP6 showed significant dual-efficacy against hyperlipidemia and obesity in high-fat diet mice by inhibiting lipid synthesis and regulating gut microbiota. These findings highlight the potential and generalizability of Deepeptide in therapeutic oligopeptide discovery for metabolic diseases.

Abstract Introduction Cannabidiol has been shown to exert significant anti-inflammatory effects and has demonstrated efficacy in murine models of autoimmune myocarditis, pericarditis, and heart failure. The ARCHER Study assessed whether a pharmaceutically produced cannabidiol formulation showed beneficial effects on cardiac magnetic resonance (CMR) endpoints known to predict prognosis in this patient population. Methods In a multicentre international double-blind placebo-controlled phase 2 study, we randomly assigned 109 patients within 10 days of CMR confirmed diagnosis of acute myocarditis to 12 weeks of pharmaceutically produced oral cannabidiol (active) or placebo. Dose was titrated up to 10 mg/kg of body weight twice daily. Primary endpoints were the difference in extracellular volume (ECV) and global longitudinal strain (GLS) measured by CMR at week 12. Other CMR endpoints included left-ventricular ejection fraction (LVEF), LV mass, intracellular volume (ICV), LV end-diastolic and end-systolic volumes (LVEDV, LVESV), and left-atrial end-systolic volume (LAESV). Results All randomized patients (56 active/53 placebo) completed the study with no loss to follow-up. Study drug appeared safe and well tolerated. Baseline mean ECV 38.9 ± 10.9 ml, GLS −15.3 ± 3.6%, and LVEF 60.6 ± 9.9% were consistent with mild to moderate myocarditis and predominantly intact LV function. Week 12 mean ECV was 33.6 ml in the active group and 37.3 ml in the placebo group, a difference of −3.7 ml, confidence interval (CI): −7.4 to 0.1; P = .0538; GLS was −16.0% in the active group and −15.9% in the placebo group, difference of −0.1, CI: −1.2 to 1.1; P = .90. Left ventricular mass was significantly reduced in the active group at 121.1 g compared to placebo 130.3 g, a difference of −9.2, CI: −16.4 to −2.1; P = .0117. In terms of remodelling, LAESV was significantly reduced in the active group (−8.1 ml; P = .0376) while the reduction in LVEDV failed to reach significance (−7.4 ml; P = .098). Conclusion In mild-to-moderate acute myocarditis, treatment with pharmaceutically manufactured cannabidiol was not associated with a statistically significant change in myocardial ECV or GLS, although a trend towards reduction in ECV was observed. In addition, improvement in other potential markers of myocardial recovery, including a significant reduction in LV mass, was seen in the active treatment group. Further investigation of the therapeutic potential of this therapy in inflammatory cardiac conditions is warranted.

Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.