Infertility and subfertility are significant reproductive challenges in cattle, often linked to genetic factors. Among these genetic factors, the bovine Y-linked gene family, PRAMEY, has emerged as a candidate due to its involvement in germ cell formation, fertilization, and embryonic development. This study investigates PRAMEY's role in sperm-egg binding, acrosome integrity, and epigenetic modifications during fertilization and early embryogenesis. Using IVF with bovine spermatozoa treated with either PRAMEY antibody (ab) or rabbit IgG control, we assessed sperm-egg binding and acrosome integrity at 2, 4, and 6 h post-fertilization (hpf). PRAMEY ab treatment doubled sperm binding per oocyte across all time points, with a significant increase at 6 hpf (P ≤ 0.05), although no differences in acrosome integrity were observed (P > 0.05). To explore PRAMEY's role in epigenetic regulation, we analyzed DNA (5-methylcytosine (5-mC)) and histone (H3K9me3 and H3K27me3) methylation in zygotes and embryos using immunofluorescent staining techniques. Zygotes derived from PRAMEY ab-treated spermatozoa showed significantly reduced DNA methylation in paternal pronuclei at 10 hpf and maternal pronuclei at 25 hpf (P ≤ 0.01). Histone methylation analysis revealed no significant differences in H3K9me3 methylation between groups, but H3K27me3 methylation was significantly lower in embryos produced using PRAMEY ab-treated spermatozoa at the 8-cell and morula stages (P ≤ 0.05). In summary, PRAMEY inhibition enhances sperm-egg binding and influences DNA and histone methylation dynamics in bovine embryos, underscoring its potential role in fertilization and early embryonic epigenetic regulation.

Puberty is a key phase of growth and development, characterized by psychophysical transformations. It is driven by a combination of genetic, hormonal, and environmental variables. Epigenetic mechanisms, including histone post-translational modifications and chromatin remodeling, microRNAs, and DNA methylation, play important roles in orchestrating the developmental processes. We describe environmental factors that may interact with genetics, and factors influencing puberty onset, focusing in particular on epigenetic mechanisms that can help understand the timing and variations that lead to precocious or delayed puberty.

We conducted a narrative review of associations between puberty and epigenetic mechanisms through a comprehensive search of PubMed, Scopus, and Web of Science databases.

The chromatin landscape of genes as KISS1 has revealed dynamic changes in histone modifications as puberty approaches, influencing the stimulation or inhibition of gene expression critical for reproductive maturation. MiRNAs regulate gene expression, whereas DNA methylation affects activation or repression of gene transcription of genes involved in pubertal timing. Moreover, studies in animal models have provided insights into the role of DNA methylation and miRNAs in brain sexual differentiation, highlighting the active involvement of epigenetic mechanisms in shaping sexually dimorphic brain structures.

This review highlights the importance of understanding the complex interplay between epigenetic regulation and pubertal development, which can lead to new therapeutic options and shed light on the fundamental processes driving reproductive maturation.

Polycomb repressive complexes PRC1 and PRC2 control lineage-specific gene silencing during early embryogenesis. To better understand Polycomb biology, we profile the proximal interactome (proxeome) of multiple PRC1 and PRC2 subunits in mouse embryonic stem cells (mESCs). This analysis identifies >100 proteins proximal to PRC1 and PRC2, including transcription factors and RNA-binding proteins. Notably, approximately half of the PRC2 interactors overlap with PRC1. Pluripotency-associated factors, including NANOG, colocalize with PRC2 at specific genomic sites. Following PRC2 disruption, NANOG relocalizes to other genomic regions. Interestingly, we identify PRC1 members in PRC2 proxeomes but not reciprocally. This suggests that PRC1 and PRC2 may have independent functions in addition to their cooperative roles in establishing H3K27me3-marked chromatin domains. Finally, we compare PRC2 proxeomes across different cellular contexts, including ground-state mESCs, serum-cultured mESCs, and embryoid bodies. These analyses provide a comprehensive resource, enhancing our understanding of Polycomb biology and its dynamic role across developmental states.

VERNALIZATION2 (VRN2) is a flowering plant-specific subunit of the polycomb-repressive complex 2 (PRC2), a conserved eukaryotic holoenzyme that represses gene expression by depositing the histone H3 lysine 27 trimethylation (H3K27me3) mark in chromatin. Previous work established VRN2 as an oxygen-regulated target of the N-degron pathway that may function as a sensor subunit connecting PRC2 activity to the perception of endogenous and environmental cues. Here, we show that VRN2 is enriched in the hypoxic shoot apex and emerging leaves of Arabidopsis, where it negatively regulates growth by establishing a stable and conditionally repressed chromatin state in key PHYTOCHROME INTERACTING FACTOR (PIF)-regulated genes that promote cell expansion. This function is required to keep these genes poised for repression via a light-responsive signaling cascade later in leaf development. Thus, we identify VRN2-PRC2 as a core component of a developmentally and spatially encoded epigenetic mechanism that coordinates plant growth through facilitating the signal-dependent suppression of PIF signaling.

Heat shock protein 40s (HSP40s) are a group of J domain proteins (JDPs), which serve as co-chaperones for heat shock protein 70s. We previously reported that over-expression of a soybean class C JDP, GmHSP40.1, in Arabidopsis activated defense responses. Surprisingly, a significantly delayed flowering phenotype was also observed for the GmHSP40.1-overexpressing (OE) lines. We provided evidence that the late-flowering phenotype observed in the GmHSP40.1-OE lines was not due to impaired pri-miRNA processing and pre-mRNA splicing. Instead, we found that GmHSP40.1 interacted and co-localized with both EMF1 and JMJ14, two major components in the EMF1 complex (EMF1c), which plays a key role in depositing and maintaining the H3K27me3 modification in the FT locus. Consistent with these interactions, the H3K27me3 modification at FT chromatin was significantly increased, whereas the H3K27me3 modification at FLC locus was significantly decreased in the GmHSP40.1-OE line compared with the wde-type Col-0. Interestingly, the H3K4me3 modification was just opposite to H3K27me3 modification at FT and FLC loci, suggesting an antagonistic relationship between these two modifications. Accordingly, the expression of FT and FLC was significantly reduced and increased, respectively, in the GmHSP40.1-OE line compared with that of Col-0. Lastly, we showed that both EMF1 and JMJ14 are genetically epistatic to GmHSP40.1-overexpression. Together, our results revealed that GmHSP40.1 negatively regulates flowering time through promoting the function of EMF1c via interacting with both EMF1 and JMJ14.

Chromosomes 5 and 7 are large chromosomes that contain close to 1,000 genes each. Deletions of the long arms or loss of the entire chromosome (monosomy) are common defects in myeloid disorders, particularly MDS and AML. Loss of material from either chromosome 5 or 7 results in haploinsufficiency of multiple genes, with some implicated in leukemogenesis. Abnormalities of one or both occur in up to 15% of MDS and AML cases and co-segregate in half of these. Generally, these chromosomal abnormalities are harbingers of adverse risk in both myeloid disorders. A notable exception is del(5q) in 5q- syndrome, a subtype of MDS. In this review, we describe the pathogenesis and genetic consequences of deletions in chromosomes 5 and 7. Furthermore, we provide an overview of current testing methodologies used in the assessment of these chromosomal defects in hematological malignancies and describe the disease associations and prognostic implications of aberrations in chromosomes 5 and 7 in both MDS and AML.

WD-repeat containing protein 26 (WDR26) is an essential component of the CTLH E3 ligase complex. Mutations in WDR26 lead to Skraban-Deardorff, an intellectual disability syndrome with clinical features resembling other disorders arising from defects in transcriptional regulation and chromatin structure. However, the role of WDR26 and its associated CTLH complex in regulating chromatin or transcription has not been elucidated. Here, we assessed how loss of WDR26 affects chromatin accessibility and gene expression. Transcriptome analysis of WDR26 knockout HeLa cells revealed over 2000 differentially expressed genes, while ATAC-Seq analysis showed over 32,000 differentially accessible chromatin regions, the majority mapping to intergenic and intronic regions and 13 % mapping to promoters. Above all, we found that WDR26 loss affected expression of genes regulated by AP-1 and NF-1 transcription factors and resulted in dramatic changes in their chromatin accessibility. Overall, our analyses implicate WDR26 and the CTLH complex in chromatin regulation.

Globally, the incidence and death rates associated with cancer persist in rising, despite considerable advancements in cancer therapy. Although some malignancies are manageable by a mix of chemotherapy, surgery, radiation, and targeted therapy, most malignant tumors either exhibit poor responsiveness to early identification or endure post-treatment survival. The prognosis for prostate cancer (PCa) is unfavorable since it is a perilous and lethal malignancy. The capacity of phytochemical and nutraceutical chemicals to repress oncogenic lncRNAs and activate tumor suppressor lncRNAs has garnered significant attention as a possible strategy to diminish the development, proliferation, metastasis, and invasion of cancer cells. A potential technique to treat cancer and enhance the sensitivity of cancer cells to existing conventional therapies is the use of phytochemicals with anticancer characteristics. Functional studies indicate that lncRNAs modulate drug resistance, stemness, invasion, metastasis, angiogenesis, and proliferation via interactions with tumor suppressors and oncoproteins. Among them, numerous lncRNAs, such as HOTAIR, PlncRNA1, GAS5, MEG3, LincRNA-21, and POTEF-AS1, support the development of PCa through many molecular mechanisms, including modulation of tumor suppressors and regulation of various signal pathways like PI3K/Akt, Bax/Caspase 3, P53, MAPK cascade, and TGF-β1. Other lncRNAs, in particular, MALAT-1, CCAT2, DANCR, LncRNA-ATB, PlncRNA1, LincRNA-21, POTEF-AS1, ZEB1-AS1, SChLAP1, and H19, are key players in regulating the aforementioned processes. Natural substances have shown promising anticancer benefits against PCa by altering essential signaling pathways. The overexpression of some lncRNAs is associated with advanced TNM stage, metastasis, chemoresistance, and reduced survival. LncRNAs possess crucial clinical and transitional implications in PCa, as diagnostic and prognostic biomarkers, as well as medicinal targets. To impede the progression of PCa, it is beneficial to target aberrant long non-coding RNAs using antisense oligonucleotides or small interfering RNAs (siRNAs). This prevents them from transmitting harmful messages. In summary, several precision medicine approaches may be used to rectify dysfunctional lncRNA regulatory circuits, so improving early PCa detection and eventually facilitating the conquest of this lethal disease. Due to their presence in biological fluids and tissues, they may serve as novel biomarkers. Enhancing PCa treatments mitigates resistance to chemotherapy and radiation.

DNA replication, a fundamental process in all living organisms, proceeds with continuous synthesis of the leading strand by DNA polymerase ε (Pol ε) and discontinuous synthesis of the lagging strand by polymerase δ (Pol δ). This inherent asymmetry at each replication fork necessitates the development of methods to distinguish between these two nascent strands in vivo. Over the past decade, strand-specific sequencing strategies, such as enrichment and sequencing of protein-associated nascent DNA (eSPAN) and Okazaki fragment sequencing (OK-seq), have become essential tools for studying chromatin replication in eukaryotic cells. In this review, we outline the foundational principles underlying these methodologies and summarize key mechanistic insights into DNA replication, parental histone transfer, epigenetic inheritance, and beyond, gained through their applications. Finally, we discuss the limitations and challenges of current techniques, highlighting the need for further technological innovations to better understand the dynamics and regulation of chromatin replication in eukaryotic cells.

Polycomb Repressive Complex 1 (PRC1) is a family of epigenetic regulators critical for mammalian development. Elucidating PRC1 composition and function across cell types and developmental stages is key to understanding the epigenetic regulation of cell fate determination. In this study, we discovered POGZ, a prominent Autism Spectrum Disorder (ASD) risk factor, as a novel component of PRC1.6, forming the PRC1.6-POGZ complex. Functional assays revealed that POGZ elicits transcriptional repression that is dependent on RING1B expression. Analysis of publicly available ChIP-Seq data showed that POGZ highly colocalizes with RING1B and HP1γ, two PRC1.6 components, at genes involved in multiple aspects of transcriptional regulation in the embryonic mouse cortex. Although Pogz knockout (KO) does not compromise stem cell pluripotency, Pogz ablation in neuronal progenitor cells (NPCs) led to widespread transcriptomic dysregulation with failed activation of key neuronal genes. Finally, we demonstrated that PRC1.6-POGZ regulates neuronal differentiation by repressing the bone morphogenetic protein (BMP) signaling pathway. These findings reveal a mechanism by which PRC1 and POGZ coordinate transcriptional regulation during neuronal differentiation, which offers insights into how disruptions in this pathway may contribute to neurodevelopmental disorders such as ASD.

The transition from vegetative to reproductive growth is essential for the flowering process of plants. In summer chrysanthemum, CmBBX8 exploits prominence function in floral transition by activating the expression of CmFTL1. However, how CmBBX8 induces CmFTL1 during the photoperiod inductive cycles remains unknown. Here, we show that CmBBX8 interacts with the SGS3-like protein CmFDM2, and the CmFDM2 overexpression strains presented early flowering, while knockdown strains delayed flowering. Additionally, CmFDM2 could bind to the CmFTL1 promoter and activate the expression of CmFTL1, and associate with chromatin remodeling factor CmSWI3B, and CmBBX8 induces flowering dependent on CmFDM2 and CmSWI3B. CmFDM2 also partially depends on CmSWI3B. The CmSWI3B knockdown strains exhibited a significant late flowering phenotype. Interestingly, CmBBX8 also interacts with CmSWI3B. Moreover, the level of H3K27me3 at the CmFTL1 locus was reduced when CmBBX8 and CmFDM2/CmSWI3B occupied the locus to promote chrysanthemum flowering during the photoperiod inductive cycles, which was accompanied by the increasing level of CmFTL1 transcripts. Thus, our work provides novel insights into the gradually increasing level of CmFTL1 for the floral transition through CmBBX8 recruiting chromatin modifiers CmFDM2/CmSWI3B.

Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing of transposable elements and repetitive sequences. Maintaining heterochromatin is crucial for ensuring genomic integrity and stability during the cell cycle. During meiosis, heterochromatin is important for homologous chromosome synapsis, recombination, and segregation, but our understanding of meiotic heterochromatin formation and condensation is limited. In this review, we focus on the dynamics and features of heterochromatin and how it condenses during meiosis in plants. We also discuss how meiotic heterochromatin influences the interaction and recombination of homologous chromosomes during prophase I.

Epigenetic inheritance of silent chromatin domains is fundamental to cellular memory during embryogenesis, but it must overcome the dilution of repressive histone modifications during DNA replication1. One such modification, histone H2A lysine 119 monoubiquitination (H2AK119Ub), needs to be re-established by the Polycomb repressive complex 1 (PRC1) E3 ligase to restore the silent Polycomb domain2,3. However, the exact mechanism behind this restoration remains unknown. Here, combining cryo-electron microscopy (cryo-EM) and functional approaches, we characterize the read-write mechanism of the non-canonical PRC1-containing RYBP (ncPRC1RYBP). This mechanism, which functions as a positive-feedback loop in epigenetic regulation4,5, emphasizes the pivotal role of ncPRC1RYBP in restoring H2AK119Ub. We observe an asymmetrical binding of ncPRC1RYBP to H2AK119Ub nucleosomes, guided in part by the N-terminal zinc-finger domain of RYBP binding to residual H2AK119Ub on nascent chromatin. This recognition positions the RING domains of RING1B and BMI1 on the unmodified nucleosome side, enabling recruitment of the E2 enzyme to ubiquitinate H2AK119 within the same nucleosome (intra-nucleosome read-write) or across nucleosomes (inter-nucleosome read-write). Collectively, our findings provide key structural and mechanistic insights into the dynamic interplay of epigenetic regulation, highlighting the significance of ncPRC1RYBP in H2AK119Ub restoration to sustain repressive chromatin domains.

Stem cells are a unique class of cells that possess the ability to differentiate and self-renew, enabling them to repair and replenish tissues. To protect and maintain the potential of stem cells, the cells and the environment surrounding these cells (stem cell niche) are highly responsive and tightly regulated. However, various stresses can affect the stem cells and their niches. These stresses are both systemic and cellular and can arise from intrinsic or extrinsic factors which would have strong implications on overall aging and certain disease states. Therefore, understanding the breadth of drivers, namely epigenetic alterations, involved in cellular stress is important for the development of interventions aimed at maintaining healthy stem cells and tissue homeostasis. In this review, we summarize published findings of epigenetic responses to replicative, oxidative, mechanical, and inflammatory stress on various types of adult stem cells.

Lowered muscle regenerative capacity in the elderly greatly contributes to the development of multiple diseases. The specific roles of long noncoding RNAs (lncRNAs) in muscle regenerative capacity during aging remain unknown. Here, we identify an elevated lncRNA (lncRNA-3), in association with reduced MyoD expression and suppressed muscle regenerative capacity, in the skeletal muscle of aged mice. LncRNA-3 could interact with both the MyoD1 promoter and RbAp46/48, a subunit of Polycomb repressive complex 2 (PRC2). LncRNA-3 could recruit PRC2 to the MyoD1 promoter and enhance the MyoD1 silencing, which, in turn, suppressed the muscle regenerative capacity. Muscle-specific lncRNA-3 knockdown could restore the muscle regenerative capacity in the aged mice. Exogenous RbAp46/48 binding motif (Rb-motif-2) treatment in skeletal muscle could compete for the lncRNA-3 binding, and therefore, enhance the muscle regenerative capacity in the aged mice. Taken together, lncRNA-3 requires PRC2 for MyoD1 silencing to suppress muscle regenerative capacity during aging. These findings provide a novel therapeutic target and a new strategy to elevate the muscle regenerative capacity in the aged population.

Culex pipiens, the northern house mosquito, is a major vector of West Nile virus. To survive the severe winter, adult mosquitoes enter a diapause programme. Extended lifespan and an increase in lipid storage are key indicators of diapause. Post-translational modifications to histone proteins impact the expression of genes and have been linked to the lifespan and energy utilisation of numerous insects. Here, we investigated the potential contribution of epigenetic alterations in initiating diapause in this mosquito species. Multiple sequence alignment of H3 sequences from other insect species demonstrates a high conservation of the H3 histone in Cx. pipiens throughout evolution. We then compared the levels of histone methylation in the ovaries and fat body tissues of diapausing and non-diapausing Cx. pipiens using western blots. Our data indicate that histone methylation levels in the ovaries of Cx. pipiens do not change during diapause. In contrast, H3K27me2 levels decrease more than twofold in the fat body of diapausing mosquitoes relative to non-diapausing counterparts. H3K27 methylation plays a crucial role in chromosome activation and inactivation during development in many insect species. This is predominantly governed by polycomb repressor complex 2. Intriguingly, a previous ChIP-seq study demonstrated that the transcription factor FOXO (Forkhead box O) targets the genes that comprise this complex. In addition, H3K27me2 exhibits dynamic abundance throughout the diapause programme in Cx. pipiens, suggesting its potential role in the initial activation of the diapause programme. This study expands our understanding of the relationship between alterations in epigenetic regulation and diapause.

The Polycomb system has fundamental roles in regulating gene expression during mammalian development. However, how it controls transcription to enable gene repression has remained enigmatic. Here, using rapid degron-based depletion coupled with live-cell transcription imaging and single-particle tracking, we show how the Polycomb system controls transcription in single cells. We discover that the Polycomb system is not a constitutive block to transcription but instead sustains a long-lived deep promoter OFF state, which limits the frequency with which the promoter can enter into a transcribing state. We demonstrate that Polycomb sustains this deep promoter OFF state by counteracting the binding of factors that enable early transcription pre-initiation complex formation and show that this is necessary for gene repression. Together, these important discoveries provide a rationale for how the Polycomb system controls transcription and suggests a universal mechanism that could enable the Polycomb system to constrain transcription across diverse cellular contexts.

Spreading of H3K27me3 is crucial for the maintenance of mitotically inheritable Polycomb-mediated chromatin silencing in animals and plants. However, how Polycomb repressive complex 2 (PRC2) accesses unmodified nucleosomes in spreading regions for spreading H3K27me3 remains unclear. Here, we show in Arabidopsis thaliana that the chromatin remodeler PICKLE (PKL) plays a specialized role in H3K27me3 spreading to safeguard cell identity during differentiation. PKL specifically localizes to H3K27me3 spreading regions but not to nucleation sites and physically associates with PRC2. Loss of PKL disrupts the occupancy of the PRC2 catalytic subunit CLF in spreading regions and leads to aberrant dedifferentiation. Nucleosome density increase endowed by the ATPase function of PKL ensures that unmodified nucleosomes are accessible to PRC2 catalytic activity for H3K27me3 spreading. Our findings demonstrate that PKL-dependent nucleosome compaction is critical for PRC2-mediated H3K27me3 read-and-write function in H3K27me3 spreading, thus revealing a mechanism by which repressive chromatin domains are established and propagated.

Epigenetic modifications are crucial for plant development. EFD (Exine Formation Defect) encodes a SAM-dependent methyltransferase that is essential for the pollen wall pattern formation and male fertility in Arabidopsis. In this study, we find that the expression of DRM2, a de novo DNA methyltransferase in plants, complements for the defects in efd, suggesting its potential de novo DNA methyltransferase activity. Genetic analysis indicates that EFD functions through HB21, as the knockout of HB21 fully restores fertility in efd mutants. DNA methylation and histone modification analyses reveal that EFD represses the transcription of HB21 through epigenetic mechanisms. Additionally, we demonstrate that HB21 directly represses the expression of genes crucial for pollen formation and anther dehiscence, including CalS5, RPG1/SWEET8, CYP703A2 and NST2. Collectively, our findings unveil a double negative regulatory cascade mediated by epigenetic modifications that coordinates anther development, offering insights into the epigenetic regulation of this process.

Gastric cancer (GC) is a complex disease with various etiologies. While Helicobacter pylori infection is still one of the leading risk factors for GC, increasing evidence suggests a link between GC and other infective agents such as Epstein Bar Virus (EBV). EBV-associated gastric cancer (EBVaGC) is now recognized as a distinct subgroup of GC, and the complex interactions between the virus and gastric mucosa may influence its development. A recent integrative analysis of the genome and proteome of GC tissues by The Cancer Genome Atlas project has identified EBVaGC as a specific subtype characterized by PIK3CA and ARID1A mutations, extensive DNA hyper-methylation, and activation of immune signaling pathways. These molecular characteristics are markers of the unique molecular profile of this subset of GC and are potential targets for therapy. This review aims to provide an overview of the current knowledge on EBVaGC. It will focus on the epidemiology, clinic-pathological features, and genetic characteristics of EBVaGC. Additionally, it will discuss recent data indicating the potential use of EBV infection as a predictive biomarker of response to chemotherapy and immune checkpoint inhibitors. The review also delves into potential therapeutic approaches for EBVaGC, including targeted therapies and adoptive immunotherapy, highlighting the promising potential of EBV as a therapeutic target.

Polycomb groups (PcGs) are transcriptional repressors, formed by a complex of several proteins, involved in multicellular development and cancer epigenetics. One of these proteins is the E3 ubiquitin-protein ligase RING1 (or RING1B), associated with the regulation of transcriptional repression and responsible for monoubiquitylation of the histone H2A. On the other hand, PADI4 is one of the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline, and it is also involved in the development of glioblastoma, among other types of cancers. In this work, we showed the association of PADI4 and RING1B in the nucleus and cytosol in several cancer cell lines by using immunofluorescence and proximity ligation assays. Furthermore, we demonstrated that binding was hampered in the presence of GSK484, an enzymatic PADI4 inhibitor, suggesting that RING1B could bind to the active site of PADI4, as confirmed by protein-protein docking simulations. In vitro and in silico findings showed that binding to PADI4 occurred for the isolated fragments corresponding to both the N-terminal (residues 1-221) and C-terminal (residues 228-336) regions of RING1B. Binding to PADI4 was also hampered by GSK484, as shown by isothermal titration calorimetry (ITC) experiments for the sole N-terminal region, and by both NMR and ITC for the C-terminal one. The dissociation constants between PADI4 and any of the two isolated RING1B fragments were in the low micromolar range (~2-10 μM), as measured by fluorescence and ITC. The interaction between RING1B and PADI4 might imply citrullination of the former, leading to several biological consequences, as well as being of potential therapeutic relevance for improving cancer treatment with the generation of new antigens.

This review article critically examines the pivotal role of chromatin organization in gene regulation, cellular differentiation, disease progression and aging. It explores the dynamic between the euchromatin and heterochromatin, coded by a complex array of histone modifications that orchestrate essential cellular processes. We discuss the pathological impacts of chromatin state misregulation, particularly in cancer and accelerated aging conditions such as progeroid syndromes, and highlight the innovative role of epigenetic therapies and artificial intelligence (AI) in comprehending and harnessing the histone code toward personalized medicine. In the context of aging, this review explores the use of AI and advanced machine learning (ML) algorithms to parse vast biological datasets, leading to the development of predictive models for epigenetic modifications and providing a framework for understanding complex regulatory mechanisms, such as those governing cell identity genes. It supports innovative platforms like CEFCIG for high-accuracy predictions and tools like GridGO for tailored ChIP-Seq analysis, which are vital for deciphering the epigenetic landscape. The review also casts a vision on the prospects of AI and ML in oncology, particularly in the personalization of cancer therapy, including early diagnostics and treatment optimization for diseases like head and neck and colorectal cancers by harnessing computational methods, AI advancements and integrated clinical data for a transformative impact on healthcare outcomes.

Plakophilin 1 (PKP1), a member of the p120ctn subfamily of the armadillo (ARM)-repeat-containing proteins, is an important structural component of cell-cell adhesion scaffolds although it can also be ubiquitously found in the cytoplasm and the nucleus. RYBP (RING 1A and YY1 binding protein) is a multifunctional intrinsically disordered protein (IDP) best described as a transcriptional regulator. Both proteins are involved in the development and metastasis of several types of tumors. We studied the binding of the armadillo domain of PKP1 (ARM-PKP1) with RYBP by using in cellulo methods, namely immunofluorescence (IF) and proximity ligation assay (PLA), and in vitro biophysical techniques, namely fluorescence, far-ultraviolet (far-UV) circular dichroism (CD), and isothermal titration calorimetry (ITC). We also characterized the binding of the two proteins by using in silico experiments. Our results showed that there was binding in tumor and non-tumoral cell lines. Binding in vitro between the two proteins was also monitored and found to occur with a dissociation constant in the low micromolar range (~10 μM). Finally, in silico experiments provided additional information on the possible structure of the binding complex, especially on the binding ARM-PKP1 hot-spot. Our findings suggest that RYBP might be a rescuer of the high expression of PKP1 in tumors, where it could decrease the epithelial-mesenchymal transition in some cancer cells.

High-grade glioma (HGG) is the most common cause of cancer death in children and the most common primary central nervous system tumor in adults. While pediatric HGG was once thought to be biologically similar to the adult form of disease, research has shown these malignancies to be significantly molecularly distinct, necessitating distinct approaches to their clinical management. However, emerging data have shown shared molecular events in pediatric and adult HGG including the histone H3K27M mutation. This somatic missense mutation occurs in genes encoding one of two isoforms of the Histone H3 protein, H3F3A (H3.3), or HIST1H3B (H3.1), and is detected in up to 80% of pediatric diffuse midline gliomas and in up to 60% of adult diffuse gliomas. Importantly, the H3K27M mutation is associated with poorer overall survival and response to therapy compared to patients with H3 wild-type tumors. Here, we review the clinical features and biological underpinnings of pediatric and adult H3K27M mutant glioma, offering a groundwork for understanding current research and clinical approaches for the care of patients suffering with this challenging disease.

During early development, sea lamprey embryos undergo programmatic elimination of DNA from somatic progenitor cells in a process termed programmed genome rearrangement (PGR). Eliminated DNA eventually becomes condensed into micronuclei, which are then physically degraded and permanently lost from the cell. Previous studies indicated that many of the genes eliminated during PGR have mammalian homologs that are bound by polycomb repressive complex (PRC) in embryonic stem cells. To test whether PRC components play a role in the faithful elimination of germline-specific sequences, we used a combination of CRISPR/Cas9 and lightsheet microscopy to investigate the impact of gene knockouts on early development and the progression through stages of DNA elimination. Analysis of knockout embryos for the core PRC2 subunits EZH, SUZ12, and EED show that disruption of all three genes results in an increase in micronucleus number, altered distribution of micronuclei within embryos, and an increase in micronucleus volume in mutant embryos. While the upstream events of DNA elimination are not strongly impacted by loss of PRC2 components, this study suggests that PRC2 plays a role in the later stages of elimination related to micronucleus condensation and degradation. These findings also suggest that other genes/epigenetic pathways may work in parallel during DNA elimination to mediate chromatin structure, accessibility, and the ultimate loss of germline-specific DNA.

Polycomb repressive complex 2 (PRC2) is reported to bind to many RNAs and has become a central player in reports of how long non-coding RNAs (lncRNAs) regulate gene expression. Yet, there is a growing discrepancy between the biochemical evidence supporting specific lncRNA-PRC2 interactions and functional evidence demonstrating that PRC2 is often dispensable for lncRNA function. Here, we revisit the evidence supporting RNA binding by PRC2 and show that many reported interactions may not occur in vivo. Using denaturing purification of in vivo crosslinked RNA-protein complexes in human and mouse cell lines, we observe a loss of detectable RNA binding to PRC2 and chromatin-associated proteins previously reported to bind RNA (CTCF, YY1, and others), despite accurately mapping bona fide RNA-binding sites across others (SPEN, TET2, and others). Taken together, these results argue for a critical re-evaluation of the broad role of RNA binding to orchestrate various chromatin regulatory mechanisms.

Numerous studies have shown that Schistosoma japonicum infection correlates with an increased risk of liver hepatocellular carcinoma (LIHC). However, data regarding the role of this infection in LIHC oncogenesis are scarce. This study aimed to investigate the potential mechanisms of hepatocarcinogenesis associated with Schistosoma japonicum infection.

By examining chronic liver disease as a mediator, we identified the genes contributing to Schistosoma japonicum infection and LIHC. We selected 15 key differentially expressed genes (DEGs) using weighted gene co-expression network analysis (WGCNA) and random survival forest models. Consensus clustering revealed two subgroups with distinct prognoses. Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression identified six prognostic DEGs, forming an Schistosoma japonicum infection-associated signature for strong prognosis prediction. This signature, which is an independent LIHC risk factor, was significantly correlated with clinical variables. Four DEGs, including BMI1, were selected based on their protein expression levels in cancerous and normal tissues. We confirmed BMI1's role in LIHC using Schistosoma japonicum-infected mouse models and molecular experiments.

We identified a series of DEGs that mediate schistosomiasis, the parasitic disease caused by Schistosoma japonicum infection, and hepatocarcinogenesis, and constructed a suitable prognostic model. We analyzed the mechanisms by which these DEGs regulate disease and present the differences in prognosis between the different genotypes. Finally, we verified our findings using molecular biology experiments.

Bioinformatics and molecular biology analyses confirmed a relationship between schistosomiasis and liver hepatocellular cancer. Furthermore, we validated the role of a potential oncoprotein factor that may be associated with infection and carcinogenesis. These findings enhance our understanding of Schistosoma japonicum infection's role in LIHC carcinogenesis.

Sirtuin 3 (SIRT3) regulates mitochondrial function as a mitochondrial deacetylase during oxidative stress. However, the specific regulatory mechanism and function of SIRT3 in radioresistant cancer cells are unclear. In this study, we aim to investigate how SIRT3 determines the susceptibility to glucose deprivation and its regulation in p53-based radioresistant head and neck cancer cells. We observed mitochondrial function using two established isogenic radioresistant subclones (HN3R-A [p53 null] and HN3R-B [p53 R282W]) with intratumoral p53 heterogeneity. Cell counting analysis was performed to evaluate cell proliferation and cell death. The correlation between the regulation of SIRT3 and enhancer of zeste homolog 2 (EZH2) was confirmed by immunoblotting and chromatin immunoprecipitation assay. p53-deficient radioresistant cells (HN3R-A) expression reduced SIRT3 levels and increased sensitivity to glucose deprivation due to mitochondrial dysfunction compared to other cells. In these cells, activation of SIRT3 significantly prevented glucose deprivation-induced cell death, whereas the loss of SIRT3 increased the susceptibility to glucose deficiency. We discovered that radiation-induced EZH2 directly binds to the SIRT3 promoter and represses the expression. Conversely, inhibiting EZH2 increased the expression of SIRT3 through epigenetic changes. Our findings indicate that p53-deficient radioresistant cells with enhanced EZH2 exhibit increased sensitivity to glucose deprivation due to SIRT3 suppression. The regulation of SIRT3 by EZH2 plays a critical role in determining the cell response to glucose deficiency in radioresistant cancer cells. Therefore, EZH2-dependent SIRT3 could be used as a predictive biomarker to select treatment options for patients with radiation-resistance.

The eukaryotic genome is mainly transcribed into non-coding RNAs (ncRNAs), including different RNA biotypes, such as micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), among others. Although miRNAs are assumed to act primarily in the cytosol, mature miRNAs have been reported and functionally characterized in the nuclei of different cells. Further, lncRNAs are important regulators of different biological processes in the cell nucleus as part of different ribonucleoprotein complexes. CircRNAs constitute a relatively less-characterized RNA biotype that has a circular structure as result of a back-splicing process. However, circRNAs have recently attracted attention in different scientific fields due to their involvement in various biological processes and pathologies. In this review, we will summarize recent studies that link to cancer miRNAs that have been functionally characterized in the cell nucleus, as well as lncRNAs and circRNAs that are bound by core components of the polycomb repressive complex 2 (PRC2) or the protein fused in sarcoma (FUS), highlighting mechanistic aspects and their diagnostic and therapeutic potential.

Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach.

Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition, innovative approaches include immunotherapy, epigenetic modulation, and interference with microenvironmental mechanisms.

Diverse therapeutic strategies beyond TKIs are under investigation. Immunotherapy with interferon-α (IFN-α) shows some biological effects, although further research is needed for optimal application in enhancing discontinuation rates. Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment.

Polycomb Repressive Complexes (PRCs) control gene expression through the incorporation of H2Aub and H3K27me3. In recent years, there is increasing evidence of the complexity of PRCs' interaction networks and the interplay of these interactors with PRCs in epigenome reshaping, which is fundamental to understand gene regulatory mechanisms. Here, we identified UBIQUITIN SPECIFIC PROTEASE 5 (UBP5) as a chromatin player able to counteract the deposition of the two PRCs' epigenetic hallmarks in Arabidopsis thaliana. We demonstrated that UBP5 is a plant developmental regulator based on functional analyses of ubp5-CRISPR Cas9 mutant plants. UBP5 promotes H2A monoubiquitination erasure, leading to transcriptional de-repression. Furthermore, preferential association of UBP5 at PRC2 recruiting motifs and local H3K27me3 gaining in ubp5 mutant plants suggest the existence of functional interplays between UBP5 and PRC2 in regulating epigenome dynamics. In summary, acting as an antagonist of the pivotal epigenetic repressive marks H2Aub and H3K27me3, UBP5 provides novel insights to disentangle the complex regulation of PRCs' activities.

The brain and the ovaries are in a state of continuous communication [...].

Polycomb repressive complexes (PRCs) play critical roles in cell fate decisions during normal development as well as disease progression through mediating histone modifications such as H3K27me3 and H2AK119ub. How exactly PRCs recruited to chromatin remains to be fully illuminated. Here, we report that YTHDF1, the N6-methyladenine (m6 A) RNA reader that was previously known to be mainly cytoplasmic, associates with RNF2, a PRC1 protein that mediates H2AK119ub in human embryonic stem cells (hESCs). A portion of YTHDF1 localizes in the nuclei and associates with RNF2/H2AK119ub on a subset of gene loci related to neural development functions. Knock-down YTHDF1 attenuates H2AK119ub modification on these genes and promotes neural differentiation in hESCs. Our findings provide a noncanonical mechanism that YTHDF1 participates in PRC1 functions in hESCs.

The chromosomally-arrayed Hox gene family plays central roles in embryonic patterning and the specification of cell identities throughout the animal kingdom. In vertebrates, the relatively large number of Hox genes and pervasive expression throughout the body has hindered understanding of their biological roles during differentiation. Studies on the subtype diversification of spinal motor neurons (MNs) have provided a tractable system to explore the function of Hox genes during differentiation, and have provided an entry point to explore how neuronal fate determinants contribute to motor circuit assembly. Recent work, using both in vitro and in vivo models of MN subtype differentiation, have revealed how patterning morphogens and regulation of chromatin structure determine cell-type specific programs of gene expression. These studies have not only shed light on basic mechanisms of rostrocaudal patterning in vertebrates, but also have illuminated mechanistic principles of gene regulation that likely operate in the development and maintenance of terminal fates in other systems.

Histones are subjected to extensive covalent modifications that affect inter-nucleosomal interactions as well as alter chromatin structure and DNA accessibility. Through switching the corresponding histone modifications, the level of transcription and diverse downstream biological processes can be regulated. Although animal systems are widely used in studying histone modifications, the signalling processes that occur outside the nucleus prior to histone modifications have not been well understood due to the limitations including non viable mutants, partial lethality, and infertility of survivors. Here, we review the benefits of using Arabidopsis thaliana as the model organism to study histone modifications and their upstream regulations. Similarities among histones and key histone modifiers such as the Polycomb group (PcG) and Trithorax group (TrxG) in Drosophila, Human, and Arabidopsis are examined. Furthermore, prolonged cold-induced vernalization system has been well-studied and revealed the relationship between the controllable environment input (duration of vernalization), its chromatin modifications of FLOWERING LOCUS C (FLC), following gene expression, and the corresponding phenotypes. Such evidence suggests that research on Arabidopsis can bring insights into incomplete signalling pathways outside of the histone box, which can be achieved through viable reverse genetic screenings based on the phenotypes instead of direct monitoring of histone modifications among individual mutants. The potential upstream regulators in Arabidopsis can provide cues or directions for animal research based on the similarities between them.

E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from the knockout mice, which was accompanied by a functional defect in response to T-cell receptor (TCR) stimulation. In support of a direct link between CBX4 and PD-1, Cbx4 overexpression resulted in the downregulation of Pdcd1 expression. Epigenetic analyses indicated that Cbx4 deficiency leads to diminished accumulation of inhibitory histone modifications at conserved region (CR)-C and CR-B sites of the Pdcd1 promoter, namely mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3). Moreover, inhibition of either the E3 ligase activity of polycomb-repressive complexes 1 (PRC1) or the methyltransferase activity of polycomb-repressive complexes 2 (PRC2) restores Pdcd1 expression in Cbx4-transfected cells. Cumulatively, this study reveals a novel function of CBX4 in the regulation of T-cell function and expands our understanding of the epigenetic control of Pdcd1 expression.

Circular RNAs play an important role in the development of various malignancies, including hepatocellular carcinoma (HCC). Nevertheless, the role of Hsa_circ_0093335 (circ0093335) in HCC has not yet been explored. To investigate the biological effects and molecular mechanisms of circ0093335 on HCC. Circ0093335 expression was detected in HCC cells and clinical specimens using qRT-PCR. The association between circ0093335 expression and HCC patients' clinical characteristics was determined using SPSS. The role of circ0093335 in HCC was estimated by overexpression and knockdown experiments in vitro and in vivo. qRT-PCR, nucleoplasma separation assay, FISH assay, RIP, dual luciferase reporter assay and rescue assay were used to validate the regulatory effect of circ0093335 on miR-338-5p. The study findings showed that circ0093335 was upregulated in HCC. High circ0093335 expression was linked with the tumour-node-metastasis stage and microvascular tumour invasion. circ0093335 is greatly involved in HCC cell proliferation, aggressive ability and mouse tumour growth, according to many in vitro and in vivo tests. Mechanistically, circ0093335 downregulated miR-338-5p expression by sponging, consequently promoting HCC progression. Our research indicated that circ0093335 might be a target for HCC therapy since it promotes tumour progression by acting as a miR-338-5p 'sponge'.

Abiotic stresses profoundly alter plant growth and development, resulting in yield losses. Plants have evolved adaptive mechanisms to combat these challenges, triggering intricate molecular responses to maintain tissue hydration and temperature stability during stress. A pivotal player in this defense is histone modification, governing gene expression in response to diverse environmental cues. Post-translational modifications (PTMs) of histone tails, including acetylation, phosphorylation, methylation, ubiquitination, and sumoylation, regulate transcription, DNA processes, and stress-related traits. This review comprehensively explores the world of PTMs of histones in plants and their vital role in imparting various abiotic stress tolerance in plants. Techniques, like chromatin immune precipitation (ChIP), ChIP-qPCR, mass spectrometry, and Cleavage Under Targets and Tag mentation, have unveiled the dynamic histone modification landscape within plant cells. The significance of PTMs in enhancing the plants' ability to cope with abiotic stresses has also been discussed. Recent advances in PTM research shed light on the molecular basis of stress tolerance in plants. Understanding the intricate proteome complexity due to various proteoforms/protein variants is a challenging task, but emerging single-cell resolution techniques may help to address such challenges. The review provides the future prospects aimed at harnessing the full potential of PTMs for improved plant responses under changing climate change.

Polycomb group proteins, as part of the Polycomb repressive complexes, are essential in gene repression through chromatin compaction by canonical PRC1, mono-ubiquitylation of histone H2A by non-canonical PRC1 and tri-methylation of histone H3K27 by PRC2. Despite prevalent models emphasizing tight functional coupling between PRC1 and PRC2, it remains unclear whether this paradigm indeed reflects the evolution and functioning of these complexes. Here, we conduct a comprehensive analysis of the presence or absence of cPRC1, nPRC1 and PRC2 across the entire eukaryotic tree of life, and find that both complexes were present in the Last Eukaryotic Common Ancestor (LECA). Strikingly, ~42% of organisms contain only PRC1 or PRC2, showing that their evolution since LECA is largely uncoupled. The identification of ncPRC1-defining subunits in unicellular relatives of animals and fungi suggests ncPRC1 originated before cPRC1, and we propose a scenario for the evolution of cPRC1 from ncPRC1. Together, our results suggest that crosstalk between these complexes is a secondary development in evolution.

Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes. However, the deubiquitinase responsible for genome-wide H2A deubiquitination in plants has yet to be identified. In this study, we found that the previously identified PWWP-EPCR-ARID-TRB (PEAT) complex components interact with both the ubiquitin-specific protease UBP5 and the redundant histone acetyltransferases HAM1 and HAM2 (HAM1/2) to form a larger version of PEAT complex in Arabidopsis thaliana. UBP5 functions as an H2A deubiquitinase in a nucleosome substrate-dependent manner in vitro and mediates H2A deubiquitination at the whole-genome level in vivo. HAM1/2 are shared subunits of the PEAT complex and the conserved NuA4 histone acetyltransferase complex, and are responsible for histone H4K5 acetylation. Within the PEAT complex, the PWWP components (PWWP1, PWWP2, and PWWP3) directly interact with UBP5 and are necessary for UBP5-mediated H2A deubiquitination, while the EPCR components (EPCR1 and EPCR2) directly interact with HAM1/2 and are required for HAM1/2-mediated H4K5 acetylation. Collectively, our study not only identifies dual roles of the PEAT complex in H2A deubiquitination and H4K5 acetylation but also illustrates how these processes collaborate at the whole-genome level to regulate the transcription and development in plants.