Search Results (282)

The TIP60/NuA4 complex is a large, multifunctional histone acetyltransferase assembly of ~1.7 megadaltons, composed of 17–20 subunits, which plays a central role in epigenetic regulation. Through recognition of H3K4me3 by the ING3 reader, TIP60/NuA4 is recruited to sites of active transcription, where it remodels chromatin to regulate gene expression. Its activities include histone acetylation, histone variant exchange, transcriptional co-activation, and regulation of the cell cycle and apoptosis. In this review, we examine how altered subunit levels or mutations impact the chromatin structure and transcriptional activity, and how these changes influence differentiation across diverse cell types. We emphasize the molecular mechanisms by which TIP60/NuA4 shapes lineage specification, including histone H2A and H4 acetylation by the KAT5 catalytic subunit, H2A.Z incorporation by EP400, and interactions with transcription factors such as MyoD, PPARγ, and Myc. By integrating mechanistic and functional insights, we highlight how TIP60/NuA4 acts as a central epigenetic hub in differentiation and contributes to proper developmental transitions. Full article

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies. Full article

Obesity is a multifaceted disorder influenced by various factors, with heredity being a significant contributor. Bariatric surgery is the most effective long-term intervention for morbid obesity and associated comorbidities, while outcomes vary significantly across individuals. Recent studies indicate that genetic and molecular determinants, particularly alterations in the leptin–melanocortin signalling pathway involving the fat mass and obesity-associated gene (FTO), pro-opiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), and leptin receptor (LEPR), influence the efficacy of weight loss and metabolic adaptations post-surgery. This narrative review consolidates evidence from peer-reviewed papers available in PubMed and Scopus until July 2025. The emphasis was on novel research and systematic reviews examining genetic polymorphisms, gene–environment interactions, and outcomes following bariatric procedures such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Recent research emphasised the integration of genetic screening and precision medicine models into clinical bariatric workflows. Variants in FTO (e.g., rs9939609), MC4R (e.g., rs17782313), LEPR, and POMC are associated with diminished weight loss post-surgery, an increased likelihood of weight regain, and reduced metabolic enhancement. Patients with bi-allelic mutations in MC4R, POMC, or LEPR exhibited poor long-term outcomes despite receiving effective physical interventions. Furthermore, genes regulating mitochondrial metabolism (such as PGC1A), adipokine signalling (such as ADIPOQ), and glucose regulation (such as GLP1R) have been demonstrated to influence the body’s response to sugar and the extent of weight gain or loss. Two recent systematic reviews elucidate that candidate gene investigations are beneficial; however, larger genome-wide association studies (GWAS) and machine learning techniques are necessary to enhance predictive accuracy. Integrating genetic and molecular screening with bariatric surgery planning possesses significant therapeutic potential. Genotyping can assist in patient selection, procedural decisions, and medication additions, particularly for those with variants that influence appetite regulation or metabolic flexibility. Advancements in precision medicine, including the integration of polygenic risk scores, omics-based profiling, and artificial intelligence, will enhance the customisation of surgical interventions and extend the lifespan of individuals with severe obesity. The epigenetic regulators of energy balance DNA methylation, histone changes, and microRNAs that may affect individual differences in weight-loss patterns after bariatric surgery are also briefly contextualised. We discuss the concept that epigenetic modulation of gene expression, mediated by microRNAs in response to food and exercise, may account for variations in metabolic outcomes post-surgery. Full article

High-grade gliomas (HGGs) are aggressive brain tumors with limited treatment options and poor survival outcomes. Variants including isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant, and histone 3 lysine to methionine substitution (H3K27M)-mutant subtypes demonstrate considerable tumor heterogeneity at the genetic, cellular, and microenvironmental levels. This presents a major barrier to the development of reliable models that recapitulate tumor heterogeneity, allowing for the development of effective therapies. Glioma tumor organoids (GTOs) have emerged as a promising model, offering a balance between biological relevance and practical scalability for precision medicine. In this study, we present a refined methodology for generating three-dimensional, multiregional, patient-derived GTOs across a spectrum of glioma subtypes (including primary and recurrent tumors) while preserving the transcriptomic and phenotypic heterogeneity of their source tumors. We demonstrate the feasibility of a high-throughput drug-screening platform to nominate multi-drug regimens, finding marked variability in drug response, not only between patients and tumor types, but also across regions within the tumor. These findings underscore the critical impact of spatial heterogeneity on therapeutic sensitivity and suggest that multiregional sampling is critical for adequate glioma model development and drug discovery. Finally, regional differential drug responses suggest that multi-agent drug therapy may provide better comprehensive oncologic control and highlight the potential of multiregional GTOs as a clinically actionable tool for personalized treatment strategies in HGG. Full article

Background: Germline pathogenic variants in NSD1 cause Sotos syndrome, a developmental disorder characterised by overgrowth, intellectual disability, macrocephaly, developmental anomalies, and, in some cases, tumour development. Familial cases of Sotos syndrome are rare and genotype–phenotype correlations are not well described. NSD1, a lysine-specific histone methyltransferase, is an important epigenetic regulator and pathogenic variants in NSD1 are associated with a distinctive blood DNA methylation pattern (episignature). We described a family with an NSD1 exon 3 deletion and an atypical clinical phenotype. Methods: DNA episignature profiling was undertaken with a next generation sequencing-based approach. Results: Within the family, the three affected individuals showed clinical variability with the proband being most severely affected, although none showed unequivocal macrocephaly or the characteristic facial features of Sotos syndrome. DNA methylation profiling was performed in the three affected family members, eight individuals with Sotos syndrome, and compared to control samples. The eight individuals with Sotos syndrome displayed genome-wide hypomethylation as previously described. DNA hypomethylation was also apparent in the three family members with the NSD1 exon 3 deletion with the proband being most similar to the episignature observed in confirmed Sotos syndrome patients. The two more mildly affected relatives had less pronounced DNA hypomethylation. Conclusions: A familial germline exon 3 NSD1 deletion was associated with mild Sotos syndrome phenotype with variable expressivity and a DNA methylation episignature that was less marked in milder cases than in individuals with classical Sotos syndrome. These findings support the use of methylation episignature analysis to explore intrafamilial variability in chromatin disorders. Full article

Improving ovine reproductive efficiency is an important breeding goal that could substantially enhance economic viability in the sheep industry. The histone cell cycle regulator (HIRA) gene has been functionally validated as a reproductive regulator in model organisms such as Drosophila and murine species; however, research on the effects of HIRA on the prolificacy in sheep remains scarce. Thus, this study aimed to investigate the association between genetic variants of HIRA and litter size in sheep. In brief, we identified 15 novel exonic mutations in the Sonid sheep breed via direct sequencing. Notably, a linkage disequilibrium including the c.1521C>G, c.1572C>T, and c.1578G>A mutations on exon 14 of HIRA exhibited a significant association with litter size in Sonid sheep (p < 0.01). Meanwhile, it was predicted that mutations play a major role in enhancing the stability of the mRNA secondary structure by lowering the minimum free energy, and mutations were also thought to change the mRNA secondary structure of ovine HIRA. Therefore, these findings may provide potentially useful molecular markers for optimizing reproductive performance in Sonid sheep. Full article

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

Spastic paraplegia 80 (SPG80), caused by mutations in ubiquitin-associated protein 1 (UBAP1), is a pure form of juvenile-onset hereditary spastic paraplegia (HSP) and leads to progressive motor dysfunction. Despite recent advances in the molecular analyses of HSP, disease-modifying therapy has not been established for HSP including SPG80. In the present study, we evaluated the therapeutic potential of 4-phenylbutyric acid (4-PBA), a chemical chaperone and histone deacetylase inhibitor, in Ubap1 knock-in (KI) mice expressing a disease-associated truncated UBAP1 variant. We found that 4-PBA administration significantly improved the motor performance of KI mice in the rotarod and beam walk tests, with maximal benefits achieved when given during pre- or early-symptomatic stages. Partial efficacy was also observed when treatment began after symptom onset in KI mice. Furthermore, 4-PBA attenuated spinal microglial activation and partially restored microglial morphology, although astrocytic reactivity remained unchanged. These findings support 4-PBA as a candidate therapeutic compound for SPG80 and highlight the potential of proteostasis-targeted interventions in HSPs. Full article

Histone variant macroH2A1 (mH2A1) has been widely recognized as a suppressor of gene expression. Recently, a cell cycle-dependent deposition of mH2A1 was discovered in mouse cells, but whether this process exists in human chromatin is unclear, which might be crucial for related diseases, particularly cancer. In this study, with native chromatin immunoprecipitation (nChIP-seq), we firstly demonstrate that dynamic mH2A1 domains occur in both normal and cancerous human cells and have conserved enrichment patterns across species. Our findings further provide new epigenetic insights into the role of mH2A1 in malignant proliferation, offering a novel perspective for future cancer research. Full article

p53 protein is a nuclear phosphoprotein that is a critical tumor suppressor, playing a key role in regulating the cell cycle and initiating apoptosis in response to DNA damage. As a transcription factor, it also activates genes involved in DNA repair and cell cycle arrest. H2AX is a histone H2A variant, which is vital for detecting DNA double-strand breaks. When phosphorylated at Serine 139, it forms γH2AX, which recruits DNA repair proteins to damage sites. The interaction between p53 and γH2AX is central to the DNA damage response, where p53 activates repair pathways and γH2AX flags the DNA lesions. It is known that impairing γH2AX while preserving p53 activity may slow cancer progression. Towards understanding this, graphene quantum dots (GQDs) offer a promising solution for tracking γH2AX and analyzing DNA damage, where they can help visualize it by investigating how p53 contributes to DNA repair at sites marked by γH2AX. This study examines the interactions between γH2AX and p53 with three different-sized two-layered GQDs (2 × 3 nm, 5 × 6 nm, and 8 × 9 nm) using the Molecular Dynamics (MD) approach. Our analysis revealed that both proteins adsorbed strongly to the 5 × 6 nm and 8 × 9 nm GQDs, with 5 × 6 nm GQD having the highest stability, making it a key candidate for future biosensing and cancer research, whereas the 8 × 9 nm GQD has the greatest potential to denature the proteins. Full article

Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its multifunctional nature and overexpression in several cancer types, HDAC6 has emerged as a promising therapeutic target. Methods: In this study, we employed a ligand-based pharmacophore modeling approach using a structurally diverse set of known HDAC6 inhibitors. This was followed by the virtual screening of over 140,000 commercially available compounds from both the MolPort and Asinex databases. The screening workflow incorporated pharmacophore filtering, molecular docking, and molecular dynamic (MD) simulations. Binding free energies were estimated using Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis to prioritize top candidates. A fluorometric enzymatic assay was used to measure HDAC6 activity, while cell viability assay by Cell Titer Glo was used to assess the anti-tumor activity against drug-sensitive and -resistant multiple myeloma (MM) cells. Western blotting was used to evaluate the acetylation of tubulin or histone H4 after treatment with selected compounds. Results: Three promising compounds were identified based on stable binding conformations and favorable interactions within the HDAC6 catalytic pocket. Among them, Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis identified Compound 10 (AKOS030273637) as the top theoretical binder, with a ΔG_bind value of −45.41 kcal/mol. In vitro enzymatic assays confirmed its binding to the HDAC6 catalytic domain and inhibitory activity. Functional studies on MM cell lines, including drug-resistant variants, showed that Compound 10 reduced cell viability. Increased acetylation of α-tubulin, a substrate of HDAC6, likely suggested on-target mechanism of action. Conclusions: Compound 10, featuring a benzyl 4-[4-(hydroxyamino)-4-oxobutylidene] piperidine-1-carboxylate scaffold, demonstrates potential drug-like properties and a predicted bidentate zinc ion coordination, supporting its potential as an HDAC6 inhibitor for further development in hematologic malignancies. Full article

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, spread rapidly across the globe in 2020, with most countries experiencing two distinct waves of infection. In Brazil, the second wave was marked by the emergence of the P.1 (Gamma) variant, which disproportionately affected younger individuals and was associated with increased mortality. This study aimed to evaluate the epidemiological profile and post mortem histopathological lung findings, correlate them with laboratory results, and compare the first and second waves of COVID-19. To investigate neutrophil extracellular traps (NETs), we performed immunohistochemistry for citrullinated histone H3 (cit-H3) and myeloperoxidase (MPO). Our cohort included patients who died in the intensive care unit (ICU) of a single center in southern Brazil. The study included 42 patients, 24 from the first wave and 18 from the second, who died between March 2020 and August 2021. Laboratory data included complete blood counts and D-dimer levels. Histopathological analyses were conducted using H&E-stained slides and reviewed independently by two blinded pathologists. MPO and cit-H3 immunohistochemistry were performed to evaluate NETs markers. All cases exhibited varying degrees of inflammation and diffuse alveolar damage (DAD), with frequent microvascular thrombi. Neutrophilic infiltration was significantly higher in the second wave. Additionally, cases with intense neutrophilic infiltration showed a stronger association with thrombosis. NETs were identified in 10 cases. No significant correlation was found between histopathological findings, NETs, and laboratory blood count results. The histopathological findings were consistent with those reported globally. The second wave of COVID-19 showed higher neutrophilic infiltrate in the lung tissue. Neutrophils play a key role in the inflammatory response and NET formation might indicate an increased risk of mortality. Further studies can consider NET-targeted therapies as potential strategies. Full article

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss among the elderly, and is influenced by a combination of genetic and environmental risk factors. While genetic associations in AMD are well-established, the molecular mechanisms underlying disease onset and progression remain poorly understood. A growing body of evidence suggests that epigenetic modifications may serve as a potential missing link regulating gene–environment interactions. This review incorporates recent findings on DNA methylation, including both hypermethylation and hypomethylation patterns affecting genes such as silent mating type information regulation 2 homolog 1 (SIRT1), glutathione S-transferase isoform (GSTM), and SKI proto-oncogene (SKI), which may influence key pathophysiological drivers of AMD. We also examine histone modification patterns, chromatin accessibility, the status of long non-coding RNAs (lncRNAs) in AMD pathogenesis and in regulating pathways pertinent to the pathophysiology of the disease. While the field of ocular epigenetics remains in its infancy, accumulating evidence to date points to a burgeoning role for epigenetic regulation in AMD, pre-clinical studies have yielded promising findings for the prospect of epigenetics as a future therapeutic avenue. Full article

The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. In this study, we employed isoform-specific epitope-tagged knock-in mouse embryonic stem cell (ESC) lines to dissect the roles of each isoform in Polycomb Repressive Complex 1 (PRC1)-mediated H2AK119ub. Our results show that H2AZ.1 and H2AZ.2 share highly overlapping genomic binding profiles, both co-localizing extensively with H2AK119ub-enriched loci. The knockdown of either isoform led to reduced H2AK119ub levels; however, the two isoforms appear to function through distinct mechanisms. H2AZ.1 facilitates the recruitment of Ring1B, the catalytic subunit of PRC1, thereby promoting the deposition of H2AK119ub. In contrast, H2AZ.2 does not significantly affect Ring1B recruitment but instead functions as a structural component that stabilizes H2AK119ub-modified nucleosomes. In vitro ubiquitination assays indicate that H2AZ.1-containing nucleosomes serve as more efficient substrates for PRC1-mediated ubiquitination compared to those containing H2AZ.2. Thus, these findings define the distinct mechanisms of the two H2AZ variants in regulated PRC1-mediated H2AK119 ubiquitination and highlight a functional division of labor in epigenetic regulation. Full article

Defects in lysosomal cholesterol handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann–Pick type C disease (NPCD), where cholesterol export from the endosomal–lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as new drug targets for NPCD using patient-derived skin fibroblasts. Treatment with JQ1, a prototype BET protein inhibitor, raised the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose-, time-, and patient-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by pharmacologic inhibition of NPC1 and of histone deacetylase (HDAC) activity, respectively. Taken together, bromodomain proteins should be further explored as therapeutic drug targets for lysosomal diseases like NPCD, and as new components regulating lysosomal function and cholesterol metabolism. Full article