Histone proteins are a primary component of chromatin; therefore, any modifications to their structure are anticipated to affect the behavior of our genetic material, which is manifested in the form of phenotypic changes at a molecular, cellular or organic level. The majority of histone modifications are of either methylation or acetylation type that regulate gene expression. Though, not all of these modifications are concerned with the direct regulation of gene transcription. Throughout its 13-year run, Epigenomics has never ceased to cover these most gripping epigenetic stories, a significant proportion of which is in the matter of histones and their modifications. As such, the current perspective piece is intended to highlight original histone-oriented contributions published in Epigenomics since 2020.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, associated with poor survival outcomes. Lack of early diagnosis, resistance to conventional therapeutic treatments (including immunotherapy) and recurrence are some of the major hurdles in PDAC and contribute to its poor survival rate. While the risk of genetic predisposition to cancers is widely acknowledged and understood, recent advances in whole-genome and next-generation sequencing techniques have led to the acknowledgment of the role played by epigenetics, especially in PDAC. Epigenetic changes are heritable genetic modifications that influence gene expression without altering the DNA sequence. Epigenetic mechanisms (e.g., DNA methylation, post-translational modification of histone complexes and ncRNA) that result in reversible changes in gene expression are increasingly understood to be responsible for tumor initiation, development and even escape from immune surveillance. Our review seeks to highlight the various components of the epigenetic machinery that are known to be implicated in PDAC initiation and development and the feasibility of targeting these components to identify novel pharmacological strategies that could potentially lead to breakthroughs in PDAC treatment.

Background: Seminoma is a testicular tumor type, routinely diagnosed after orchidectomy. As cfDNA represents a source of minimally invasive seminoma patient management, this study aimed to investigate whether cfDNA methylation of six genes from liquid biopsies, have potential as novel seminoma biomarkers. Materials & methods: cfDNA methylation from liquid biopsies was assessed by pyrosequencing and compared with healthy volunteers' samples. Results: Detailed analysis revealed specific CpGs as possible seminoma biomarkers, but receiver operating characteristic curve analysis showed modest diagnostic performance. In an analysis of panels of statistically significant CpGs, two DNA methylation panels emerged as potential seminoma screening panels, one in blood CpG8/CpG9/CpG10 (KITLG) and the other in seminal plasma CpG1(MAGEC2)/CpG1(OCT3/4). Conclusion: The presented data promote the development of liquid biopsy epigenetic biomarkers in the screening of seminoma patients.

miRNAs are a class of noncoding RNAs of approximately 19-22 nucleotides that are widely found in animals, plants, bacteria and even viruses. Dysregulation of the expression profile of miRNAs is importantly linked to the development of diseases. Epigenetic modifications regulate gene expression and control cellular phenotypes. Although miRNAs are used as an epigenetic regulation tool, the biogenesis of miRNAs is also regulated by epigenetic events. Here the authors review the mechanisms and roles of epigenetic modification (DNA methylation, histone modifications), RNA modification and ncRNAs in the biogenesis of miRNAs, aiming to deepen the understanding of the miRNA biogenesis regulatory network.

Aims: We aimed to determine whether intronic circRNA acts as a molecular sponge in castration-resistant prostate cancer (CRPC). Materials & methods: A gene chip technique was used to conduct sequencing. A qPCR experiment was performed to verify the result. Radioimmunoprecipitation, RNA pull-down and dual-luciferase reporter assays were performed to particularly expound its function. Verification of downstream effects was carried out through qPCR and western blot, and a xenograft assay was performed in vivo for verification. Results: Intronic circRNA hsa_circ_0092339 in the nucleus was highly expressed in CRPC cell lines. hsa_circ_0092339 did not regulate the expression of its parental gene. hsa_circ_0092339 functions like a molecular sponge, preventing degradation of C-MYC mRNA by absorbing hsa-mir-940. Conclusion: hsa_circ_0092339 plays a critical role in CRPC through targeting C-MYC indirectly by absorbing hsa-mir-940.

Background: Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Materials & methods: Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins. Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of the ABO locus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure. Conclusion: This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight.

Aims: We aim to investigate the effects of miR-421 on lipid metabolism in non-small cell lung cancer (NSCLC). Methods: The miR-421 expression and PTEN mRNA level in tumor tissues, adjacent normal tissues, human lung epithelial cells and NSCLC cell lines were detected with reverse transcription quantitative real-time PCR. Results: MiR-421 was increased, and PTEN was reduced remarkably in tumor tissues and NSCLC cell lines. Down-regulated miR-421 suppressed lipid accumulation, cell proliferation, migration and invasion, whereas overexpression of miR-421 had the opposite effects. MiR-421 directly targeted PTEN and negatively regulated PTEN expression. MiR-421 activated PI3K/AKT/mTOR pathway through regulating PTEN. Conclusion: MiR-421 promotes lipid metabolism through targeting PTEN via PI3K/AKT/mTOR pathway activation in NSCLC, indicating that miR-421 can be a latent therapeutic target for NSCLC.

The rate of substance use is rising, especially among reproductive-age individuals. Emerging evidence suggests that paternal pre-conception and maternal prenatal substance use may alter offspring epigenetic regulation (changes to gene expression without modifying DNA) and outcomes later in life, including neurodevelopment and mental health. However, relatively little is known due to the complexities and limitations of existing studies, making causal interpretations challenging. This review examines the contributions and influence of parental substance use on the gametes and potential transmissibility to the offspring's epigenome as possible areas to target public health warnings and healthcare provider counseling of individuals or couples in the pre-conception and prenatal periods to ultimately mitigate short- and long-term offspring morbidity and mortality.

EZH2, acting as a catalytic subunit of PRC2 to catalyze lysine 27 in histone H3, induces the suppression of gene expression. EZH2 can regulate cell proliferation and differentiation of retinal progenitors, which are required for physiological retinal development. Meanwhile, an abnormal level of EZH2 has been observed in ocular tumors and other pathological tissues. This review summarizes the current knowledge on EZH2 in retinal development and ocular diseases, including inherited retinal diseases, ocular tumors, corneal injury, cataract, glaucoma, diabetic retinopathy and age-related retinal degeneration. We highlight the potential of targeting EZH2 as a precision therapeutic target in ocular diseases.

Aim: This study aimed to critically appraise the evidence of the diagnostic effectiveness of miRNAs for the detection of cervical cancer. Methods & materials: A systematic review and meta-analysis was performed, searching PubMed, EMBASE and Web of Science. An umbrella meta-analysis of meta-analyses of individual biomarkers was performed. A Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment of evidence was also performed. Results: A total of 52 miRNAs were included. Umbrella meta-analysis revealed significant heterogeneity in terms of sensitivity, specificity, receiver operating characteristic (ROC), positive predictive value and/or negative predictive value. Umbrella effects were 0.76 (95% CI: 0.73-0.78), 0.78 (95% CI: 0.75-0.81), 0.77 (95% CI: 0.75-0.80), 0.75 (95% CI: 0.71-0.79) and 0.76 (95% CI: 0.74-0.79), respectively. Conclusion: Moderate quality evidence suggested miR199a-5p, miR21-5p and miR-141a had excellent diagnostic performance.

Epigenetic changes play a significant role in cancer progression, maintenance and therapy resistance. Generally, epigenetic modifications are reversible, thereby gaining attention for therapeutic interventions. However, limited efficacy and therapy resistance remain the significant limitations of conventional and epigenetic anticancer therapies. Recently, combination therapies with epigenetic drugs (epi-drugs) and conventional anticancer treatment have gained widespread attention. Here, epi-drugs are administered with anticancer therapies to increase their therapeutic efficacy and sensitize cancer cells resistant to therapies. This review summarizes the mechanism of epi-drugs in reversing resistance to anticancer therapies. Further, the challenges faced during developing combination therapies with epi-drugs are discussed. We believe the clinical benefit of combination therapies could be increased by overcoming the challenges faced during epi-drug development.

Background: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants. Epigenetic changes in DNA methylation may be present prior to NEC onset. Methods: 24 preterm infants with NEC and 45 matched controls were included. Human DNA was isolated from stool samples and methylation of CTDSPL2, HERC1, NXPE3 and PTGDR was measured using pyrosequencing. Results: CTDSPL2 displayed a higher DNA methylation of 51% compared with 17% in controls, prior to NEC onset (p = 0.047). Discussion: Noninvasive measurement of methylation in stool allows for comparison with healthy preterm controls. This potentially allows future biomarker or risk predictor use. The effect of CTDSPL2 hypermethylation on gene expression remains unclear.

We discuss pathological epigenetic events that are reversible (PEERs). A recent study by Poganik and colleagues showed that severe stress in mice and humans transiently elevates biological age of several tissues, and this transient age increase is reversible when the stress is removed. These studies suggest new strategies for reversing normal aging. However, it is important to note that developmental origin of health and disease studies have shown that developmental exposure to toxic chemicals such as lead causes permanent changes in neuron shape, connectivity and cellular hyperplasia of organs such as the heart and liver. In this review, the PEER hypothesis speculates that the hallmarks of aging and the hallmarks of developmental origin of health and disease intersect at PEERs.

Aim: To develop novel prognostic markers for early detection and prognosis of ovarian cancer (OC). Materials & methods: We utilized bioinformatics analysis to identify and construct a prognostic model consisting of lncRNAs centered around JARID2 and explored the potential ceRNA network in OC. Cell functional experiments were conducted to validate the reliability of the ceRNA network and investigate the functional role of JARID2 in OC. Results: We constructed a nomogram composed of ten lncRNAs and identified the PKD1P6/miR-424-5p/JARID2 axis. Furthermore, our findings indicated that JARID2 promotes the proliferation of SKOV3 cells, suggesting its oncogenic role in OC. Conclusion: JARID2, potentially regulated by the PKD1P6/miR-424-5p/JARID2 axis, represents a potential novel biomarker for OC.

Aim: To explore the roles of GMDS-AS1 in the epithelial-mesenchymal transition (EMT) of lung adenocarcinoma (LUAD). Materials & methods: Cell functions were detected by flow cytometry, cell counting kit-8, wound healing assays and transwell assays. RNA immunoprecipitation and pull-down assays were applied for determining the interaction among GMDA-AS1, TAF15 and SIRT1. A subcutaneous xenograft model was established. Results: GMDS-AS1 downregulation was associated with poor survival of LUAD patients. GMDS-AS1 repressed malignant phenotypes, tumor growth and EMT in vitro and in vivo. Mechanically, GMDS-AS1 recruited TAF15 protein to stabilize SIRT1 mRNA and thereby deacetylated p65 and reduced the recruitment of p65 to MMP-9 promoter, thus inhibiting MMP-9 expression. Conclusion: GMDS-AS1 represses EMT by recruiting TAF15 protein to stabilize SIRT1 mRNA and deacetylate p65, thus restraining LUAD progression.

Background: We performed an epigenome-wide longitudinal DNA methylation study on an Indian cohort of pregnant women, GARBH-Ini, at three time points during pregnancy and at delivery. Aim & objective: Our aim was to identify temporal DNA methylation changes in maternal peripheral blood during the period of gestation and assess their impact on biological pathways critical for term delivery. Results: Significantly differentially methylated CpGs were identified by linear mixed model analysis (Bonferroni p < 0.01) and classified into two distinct temporal methylation trends: increasing and decreasing during gestation. Genes with upward methylation trend were enriched for T-cell activity, while those with a downward trend were enriched for solute transport and cell structure organization functions. Conclusion: Consistent trends of DNA methylation in maternal peripheral blood point to the sentinel function of T cells in the maintenance of pregnancy, and the importance of coordinated cellular remodeling to facilitate term delivery.