Epigenetic Regulation Research Articles

Infective agents and polymyalgia rheumatica: key discussion points emerging from a narrative review of published literature

IntroductionThe aetiology of polymyalgia rheumatica (PMR) is unknown. Recently, reports on cases of PMR following the coronavirus disease 2019 (COVID-19) have revived the role of infection as an aetiological or triggering factor. It is estimated that patients with PMR have manifestations of giant cell arteritis (GCA) in < 20% of cases. To date, little is known on the potential role of infectious agents in facilitating this association. Given this background, we performed a review of published literature. Our first aim was to review and discuss the relationship between PMR and infective agents. Secondly, we compared data of PMR-only patients with PMR and overlapping GCA to seek any commonalities or differences regarding the type of infectious agent in these two subgroups.Material and MethodsWe performed a non-systematic literature search on Embase and Medline (COVID interface) with the following search terms: “polymyalgia rheumatica” AND “infections” OR “infectious agents”, both MESH headings and free-text (in each language they were written). Each paper’s reference list was scanned for additional publications meeting this study’s aim. When papers reported data partially presented in previous articles, we referred to the most recent published data. Abstracts submitted at conferences or from non-peer-reviewed sources were not included. Polymyalgia rheumatica following vaccinations was an additional exclusion criterion.ResultsSeveral infectious agents have been held responsible for PMR. However, no definite causal link has been identified so far. According to our review, the search for a specific infectious agent, however intriguing, appears to be stagnating. Genetic background and epigenetic regulation probably play a key role. However, topical studies are lacking. Polymyalgia rheumatica as an adverse event following immunization should be kept methodologically distinct from PMR following an acute infection, as the adjuvants in the vaccine can make a significant difference.ConclusionsFinally, some infectious agents are able to replicate in human arteries or have an endothelium tropism. Whilst these can theoretically trigger GCA, their role in isolated PMR seems minimal.

TNF-alpha gene promoter's hypomethylation mediates a pro-inflammatory phenotype in peripheral blood monocytes from apical periodontitis individuals.

Epigenetic regulation of the key inflammatory genes plays a crucial role in controlling monocyte/macrophage-mediated local and systemic responses to bacterial challenges. However, it has not been addressed in apical periodontitis (AP). We aimed to explore the methylation pattern of the TNF-α gene promoter and its association with the inflammatory phenotype of peripheral blood monocytes from individuals with AP and controls. A cross-sectional study was conducted, including otherwise healthy individuals with AP (n = 25) and controls (n = 29). Monocytes were isolated from the volunteer's blood samples using a Ficoll gradient followed by negative immunoselection. RNA and DNA were extracted. The DNA methylation profiles of the TNF-α gene promoter region were analyzed using bisulfite sequencing PCR. The mRNA expression levels of DNA methyltransferases 3a (DNMT3a) and Ten Eleven Translocation enzymes 1(TET1) were assessed by qPCR. A fraction of primary monocytes was also cultured for 24 h, and the supernatant was collected to measure cytokine levels through a Luminex assay. Generalized structural equation models (GSEM) evaluated the association between AP, DNA methylation, and TNF-α protein expression controlled for potential covariates. Models included the effect of the methylation of TNF-α gene promoter as a mediator of the association between AP and TNF-α protein expression levels. Monocytes from AP individuals exhibited a heightened secretion of TNF-α and IL-1β and hypomethylation of the TNF gene promoter (p < .05). AP diagnosis was associated with the TNF-α gene promoter´s hypomethylated profile and enhanced pro-inflammatory cytokine levels, while lower methylation of the gene promoter region and -163 CpG single site mediated TNF-α overexpression (p < .05). DNA hypomethylation at the TNF-α gene mediates a proinflammatory phenotype in monocytes from AP patients, supporting a role in the systemic response.

Nuclear transfer leads to aberrant cell cycle regulation and translation, as determined by gene expression, and selection of mitochondrial DNA in porcine blastocysts

Abstract Nuclear transfer technologies, such as metaphase II spindle transfer (MII-ST), are being developed to overcome poor oocyte quality and prevent children from acquiring severe mitochondrial DNA (mtDNA) disease. However, it is unclear whether these technologies perturb gene expression; and mtDNA carryover can be reduced to minimal levels. Using our pig model, we isolated individual karyoplasts with limited mtDNA carryover (306 ± 49 copies) from mature oocytes. Firstly, we reintroduced the spindle into its original cytoplast (autologous), fertilised, and cultured the resultant embryos to the hatching blastocyst stage of development. Following RNA-seq, 64 genes were differentially expressed at FDR &amp;lt; 0.05; and 1327 genes at P &amp;lt; 0.05. Pathways associated with cell cycle and epigenetic regulation and genes associated with nuclear-mitochondrial interactions were upregulated whilst protein translation pathways were downregulated. We then transferred karyoplasts to third party cytoplasts (heterologous) and undertook mtDNA next generation sequencing of 2-cell to hatching blastocyst stage preimplantation embryos. Nine of 20 embryos possessed two mitochondrial genomes. Our outcomes show that autologous nuclear transfer alone significantly changes hatching blastocyst gene expression; very low levels of mtDNA carryover can be preferentially replicated during early development; and nuclear and mitochondrial synchrony has not been reestablished.

5-Hydroxymethylcytosine: Far Beyond the Intermediate of DNA Demethylation.

Epigenetics plays a pivotal role in regulating gene expression and cellular differentiation. DNA methylation, involving the addition of methyl groups to specific cytosine bases, is a well-known epigenetic modification. The recent discovery of 5-hydroxymethylcytosine (5hmC) has provided new insights into cytosine modifications. 5hmC, derived from the oxidation of 5-methylcytosine (5mC), serves as both an intermediate in demethylation and a stable chemical modification in the genome. In this comprehensive review, we summarize the recent research advancements regarding the functions of 5hmC in development and disease. We discuss its implications in gene expression regulation, cellular differentiation, and its potential role as a diagnostic and prognostic marker in various diseases. Additionally, we highlight the challenges associated with accurately detecting and quantifying 5hmC and present the latest methodologies employed for its detection. Understanding the functional role of 5hmC in epigenetic regulation and further advancing our understanding of gene expression dynamics and cellular processes hold immense promise for the development of novel therapeutic strategies and precision medicine approaches.

Epigenetic Mechanisms Induced by Mycobacterium tuberculosis to Promote Its Survival in the Host.

Tuberculosis caused by the obligate intracellular pathogen, Mycobacterium tuberculosis, is one among the prime causes of death worldwide. An urgent remedy against tuberculosis is of paramount importance in the current scenario. However, the complex nature of this appalling disease contributes to the limitations of existing medications. The quest for better treatment approaches is driving the research in the field of host epigenomics forward in context with tuberculosis. The interplay between various host epigenetic factors and the pathogen is under investigation. A comprehensive understanding of how Mycobacterium tuberculosis orchestrates such epigenetic factors and favors its survival within the host is in increasing demand. The modifications beneficial to the pathogen are reversible and possess the potential to be better targets for various therapeutic approaches. The mechanisms, including histone modifications, DNA methylation, and miRNA modification, are being explored for their impact on pathogenesis. In this article, we are deciphering the role of mycobacterial epigenetic regulators on various strategies like cytokine expression, macrophage polarization, autophagy, and apoptosis, along with a glimpse of the potential of host-directed therapies.

Epigenomic studies in sorghum reveal differential enrichment of multiple histone marks at clade A PP2C genes in response to drought

Epigenetic regulation is essential for plant development and stress responses, as numerous stress-responsive genes are modulated epigenetically. However, most research has focused on individual histone marks. This study expands on previous work by examining the genome-wide profiles of seven histone marks (H3K9ac, H3K27ac, H3K4me3, H3K36me3, H3K27me3, H2A.Z, and H3K4me2) in sorghum leaves and roots under PEG-induced drought stress. Results revealed that five histone marks (excluding H3K36me3 and H3K27me3) were significantly associated with drought-responsive gene expression. The differential enrichment of these marks may enhance the induction of drought-responsive genes. Specifically, a subset of genes showed multiple histone marks' differential enrichment, with most clade A PP2C genes exhibiting enrichment for four marks after PEG treatment. This suggests a critical role for robust PP2C gene induction in sorghum’s drought response. Additionally, promoter cis-element analysis identified ERF family transcription factors as potential mediators of histone mark enrichment under drought conditions, providing new insights into the interaction between epigenetic modifications and transcriptional regulation in plant stress responses.

P4PC: A Portal for Bioinformatics Resources of piRNAs and circRNAs

Background: PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs) are two kinds of non-coding RNAs (ncRNAs) that play important roles in epigenetic regulation, transcriptional regulation, post-transcriptional regulation of many biological processes. Although there exist various resources, it is still challenging to select such resources for specific research projects on ncRNAs. Methods: In order to facilitate researchers in finding the appropriate bioinformatics sources for studying ncRNAs, we created a novel portal named P4PC that provides computational tools and data sources of piRNAs and circRNAs. Results: 249 computational tools, 126 databases and 420 papers are manually curated in P4PC. All entries in P4PC are classified in 5 groups and 26 subgroups. The list of resources is summarized in the first page of each group. Conclusion: According to their research proposes, users can quickly select proper resources for their research projects by viewing detail information and comments in P4PC. Database URL is http://www.ibiomedical.net/Portal4PC/ and https://43.138.46.5/Portal4PC/.

SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance.

Epigenetic modifiers (miRNAs, histone methyltransferases (HMTs)/demethylases, and DNA methyltransferases/demethylases) are associated with cancer proliferation, metastasis, angiogenesis, and drug resistance. Among these modifiers, HMTs are frequently overexpressed in various cancers, and recent studies have increasingly identified these proteins as potential therapeutic targets. In this review, we discuss members of the SET and MYND domain-containing protein (SMYD) family that are topics of extensive research on the histone methylation and nonhistone methylation of cancer-related genes. Various members of the SMYD family play significant roles in cancer proliferation, metastasis, and drug resistance by regulating cancer-specific histone methylation and nonhistone methylation. Thus, the development of specific inhibitors that target SMYD family members may lead to the development of cancer treatments, and combination therapy with various anticancer therapeutic agents may increase treatment efficacy.

Binding of PtoRAP2.12 to demethylated and accessible chromatin regions in the PtoGntK promoter stimulates growth of poplar.

DNA methylation is an essential epigenetic modification for gene regulation in plant growth and development. However, the precise mechanisms of DNA methylation remain poorly understood, especially in woody plants. We employed whole-genome bisulfite sequencing (WGBS), assays for transposase-accessible chromatin using sequencing (ATAC-seq), and RNA-Seq to investigate epigenetic regulatory relationships in Populus tomentosa treated with DNA methylation inhibitor 5-azacitidine. Expression-quantitative trait methylation analysis (eQTM), epigenome-wide association study (EWAS), and joint linkage-linkage disequilibrium mapping were used to explore the epigenetic regulatory genes, and using CRISPR/Cas9 to identify the role of candidate genes. Plant developmental abnormalities occurred when DNA methylation levels were substantially reduced. DNA methylation regulated 112 expressed genes via chromatin accessibility, of which 61 genes were significantly influenced by DNA methylation variation at the population level. One DNA methylation-regulated gene, PtoGntK, was located in a major quantitative trait locus (QTL) for poplar growth. Overexpression and CRISPR/Cas9 of PtoGntK revealed it affected poplar height and stem diameter. The PtoRAP2.12 was found to bind to the demethylated accessible region in the PtoGntK promoter, thereby promoting growth in poplar. This study identified key genes with epigenetic regulation for plant growth and provides insights into epigenetic regulation mechanisms in woody plants.

Novel Regulatory Mechanisms for Expression of Drug Metabolism-related Factors

Interindividual differences in the expression and activity of drug-metabolizing enzymes, including cytochrome P450, UDP-glucuronosyltransferase, and esterases, cause variability of therapeutic effectiveness and side effects during drug treatment. Conventional research has focused on transcriptional regulation by transcription factors and nuclear receptors such as aryl hydrocarbon receptor, pregnane X receptor (PXR), constitutive androstane receptor, and hepatocyte nuclear factor 4α, as the major mechanisms causing the differences in the expression of drug-metabolizing enzymes. Recently, we have revealed that adenosine-to-inosine RNA editing and methylation of adenosine at the N6 position on RNA, two major types of posttranscriptional modification, play a pivotal role in the regulation of drug metabolism. In addition, switch/sucrose non-fermentable complex, a chromatin remodeler, is required for PXR-mediated transcriptional regulation of drug-metabolizing enzymes. This review article introduces the significance of these epitranscriptomic and epigenetic regulations as factors in determining drug metabolism potency. Further research on this link is expected to lead to a deeper understanding of interindividual differences in the therapeutic effectiveness and side effects of medicines.

Epigenetic regulation of TGF-β and vice versa in cancers - A review on recent developments.

This review explores the complex relationship between epigenetic mechanisms and Transforming Growth Factor-beta (TGF-β) signalling pathways in the field of cancer research. The study provides an overview of the latest advancements in understanding the crucial functions of epigenetic alterations, such as DNA methylation, histone modifications, and chromatin remodeling, in significantly impacting the TGF-β signalling pathway. The dynamic epigenetic modifications are essential in determining the behaviour of cancer cells, impacting the interactions with the tumor microenvironment, and affecting the overall process of carcinogenesis. Significant attention is given to Breast cancer, Lung cancer, Liver cancer, Prostate cancer, and Pancreatic cancer. Research has revealed intricate regulatory networks in these cancers, involving long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and histone post-translational modifications. These networks are closely connected to TGF-β signalling. Both findings highlight the significant interaction between epigenetic regulation and TGF-β signalling in cancer. They provide valuable insights that can guide the development of new treatment approaches to target both pathways and prevent cancer growth and metastasis.

Genetic and epigenetic control of dormancy transitions throughout the year in the monoecious cork oak.

Bud dormancy plays a vital role in flowering regulation and fruit production, being highly regulated by endogenous and environmental cues. Deployment of epigenetic modifications and differential gene expression control bud dormancy/break cycles. Information on how these genetic and epigenetic mechanisms are regulated throughout the year is still scarce for temperate trees such as Quercus suber. Here, the expression levels of CENTRORADIALIS-LIKE (CENL) and DORMANCY-ASSOCIATED PROTEIN 1 (QsDYL1) during seasonal cycles of bud development, suggesting that QsCENL may be implicated in growth cessation in Q. suber and that QsDYL1 is a good dormancy marker. As gene expression can be regulated by the activity of chromatin modifiers, we have analysed the expression of these genes and the deposition of epigenetic marks in dormant versus non-dormant bud meristems. The DNA methyl transferases CHROMOMEHTYLASE 3 (QsCMT3) and METHYLTRANSFERASE 1 (QsMET1) were more expressed in the transition between dormancy to bud swelling. QsCMT3 was also highly expressed during the late stages of active bud formation. Conversely, the HISTONE ACETYLTRANSFERASE 1 (QsHAC1) was up-regulated during growth cessation and dormancy when compared to bud swelling. These results indicate that epigenetic regulation is implicated in how bud development progresses in Q. suber, which can be observed in the different profile deposition of the repressive and active marks, 5mC and H3K18Ac/H3K4me, respectively. The identification of bud-specific genetic and epigenetic profiling opens new possibilities to predict the relative rate of dormancy/growth of the bud stages, providing tools to understand how trees respond to the current challenges posed by climate change.

Transcriptome-based characterization of 3’2’-cGAMP signaling mediated immune responses

Cyclic dinucleotides (CDNs) are critical adjuvants in antiviral vaccines and cancer immunotherapy, primarily through the activation of the cGAS-STING signaling pathway. Evaluating the immune responses triggered by CDNs is essential for the development of effective adjuvants. In this study, we performed a comparative transcriptome analysis to characterize the immune responses elicited by the recently identified nuclease-resistant Drosophila and bacterial CDN, 3’2’-cGAMP, in mammalian immune cells. We detected a robust induction of innate immune gene signature following 3’2’-cGAMP stimulation in digitonin-permeabilized mouse primary macrophages, comparable to the response observed with the canonical mammalian CDN, 2’3’-cGAMP. STING deficiency remarkably reduced 3’2’-cGAMP-induced phosphorylation of TBK1 and IRF3 and the induction of IFN-β, indicating that 3’2’-cGAMP signaling-mediated immune responses were mainly STING dependent. In comparison to 2’3’-cGAMP signaling, 3’2’-cGAMP signaling preferentially elicited many STING-dependent genes involved in transcription and nucleosome positioning and assembly in the nucleus, which are likely associated with several enriched pathways, including cellular senescence, HDACs deacetylate histones, and epigenetic regulation of gene expression. The integrative analysis further revealed that 3’2’-cGAMP signaling preferentially induced genes were associated with autoimmune disease-related processes, suggesting a potential side effect that requires monitoring when used as an adjuvant. In conclusion, this study provides the first transcriptional landscape of 3’2’-cGAMP signaling in mammals and reveals the immune response characteristics and potential side effects mediated by 3’2’-cGAMP signaling. These findings may aid in the development of 3’2’-cGAMP-based adjuvants for antiviral vaccines and cancer immunotherapy.

Chromatin structure and 3D architecture define the differential functions of PU.1 regulatory elements in blood cell lineages

The precise spatiotemporal expression of the hematopoietic ETS transcription factor PU.1, a key determinant of hematopoietic cell fates, is tightly regulated at the chromatin level. However, how chromatin signatures are linked to this dynamic expression pattern across different blood cell lineages remains uncharacterized. Here, we performed an in-depth analysis of the relationships between gene expression, chromatin structure, 3D architecture, and trans-acting factors at PU.1 cis-regulatory elements (PCREs). By identifying phylogenetically conserved DNA elements within chromatin-accessible regions in primary human blood lineages, we discovered multiple novel candidate PCREs within the upstream region of the human PU.1 locus. A subset of these elements localizes within an 8-kb-wide cluster exhibiting enhancer features, including open chromatin, demethylated DNA, enriched enhancer histone marks, present enhancer RNAs, and PU.1 occupation, presumably mediating PU.1 autoregulation. Importantly, we revealed the presence of a common 35-kb-wide CTCF-flanked insulated neighborhood that contains the PCRE cluster (PCREC), forming a chromatin territory for lineage-specific and PCRE-mediated chromatin interactions. These include functional PCRE-promoter interactions in myeloid and B cells that are absent in erythroid and T cells. By correlating chromatin structure and 3D architecture with PU.1 expression in various lineages, we were able to attribute enhancer versus silencer functions to individual elements. Our findings provide mechanistic insights into the interplay between dynamic chromatin structure and 3D architecture in the chromatin regulation of PU.1 expression. This study lays crucial groundwork for additional experimental studies that validate and dissect the role of PCREs in epigenetic regulation of normal and malignant hematopoiesis.

NAT10-mediated RNA ac4C acetylation contributes to the myocardial infarction-induced cardiac fibrosis.

Cardiac fibrosis is featured cardiac fibroblast activation and extracellular matrix accumulation. Ac4C acetylation is an important epigenetic regulation of RNAs that has been recently discovered, and it is solely carried out by NAT10, the exclusive enzyme used for the modification. However, the potential regulatory mechanisms of ac4C acetylation in myocardial fibrosis following myocardial infarction remain poorly understood. In our study, we activated fibroblasts invitro using TGF-β1 (20 ng/mL), followed by establishing a myocardial infarction mouse model to evaluate the impact of NAT10 on collagen synthesis and cardiac fibroblast proliferation. We utilized a NAT10 inhibitor, Remodelin, to attenuate the acetylation capacity of NAT10. In the cardiac fibrosis tissues of chronic myocardial infarction mice and cultured cardiac fibroblasts (CFs) in response to TGF-β1 treatment, there was an elevation in the levels of NAT10 expression. This increase facilitated proliferation, the accumulation of collagens, as well as fibroblast-to-myofibroblast transition. Through the administration of Remodelin, we effectively reduced cardiac fibrosis in myocardial infarction mice by inhibiting NAT10's ability to acetylate mRNA. Inhibition of NAT10 resulted in changes in collagen-related gene expression and ac4C acetylation levels. Mechanistically, we found that NAT10 upregulates the acetylation modification of BCL-XL mRNA and enhances the stability of BCL-XL mRNA, thereby upregulating its protein expression, inhibiting the activation of Caspase3 and blocking the apoptosis of CFs. Therefore, the crucial involvement of NAT10-mediated ac4C acetylation is significant in the cardiac fibrosis progression, affording promising molecular targets for the treatment of fibrosis and relevant cardiac diseases.

Recent advances in noncoding RNA modifications of gastrointestinal cancer.

Elucidating the mechanisms underlying cancer development and proliferation is important for the development of therapeutic methods for the complete cure of cancer. In particular, the identification of diagnostic markers for early detection and new therapeutic strategies for refractory gastrointestinal cancers are needed. Various abnormal phenomena occur in cancer cells, such as functional changes of proteins, led by genomic mutations, and changes in gene expression due to dysregulation of epigenetic regulation. This is no exception for noncoding RNA (ncRNA), which do not encode proteins. Recent reports have revealed that microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) are deeply involved in cancer progression. These ncRNAs have attracted attention as gene expression regulatory molecules. Recent advances in technology have made it possible not only to read DNA and RNA sequences but also to study the modification state of each base. In particular, comprehensive analysis of N6-methyladenosine (m6A) has been performed by many research groups, with multiple studies reporting that m6A modifications of specific genes are associated with cancer progression. Based on the above, this review examines how ncRNA modifications are related to cancer progression in gastrointestinal cancers such as colorectal and pancreatic cancer. We also discuss enzyme inhibitors that have been reported to have drug discovery potential targeting m6A modifications. By utilizing the new perspective of ncRNA modification, we may be able to accumulate knowledge on the molecular biology of cancer and contribute to human health through diagnosis and treatment.

Pharmacological inhibition of astrocytic transglutaminase 2 facilitates the expression of a neurosupportive astrocyte reactive phenotype in association with increased histone acetylation.

Astrocytes play critical roles in supporting structural and metabolic homeostasis in the central nervous system (CNS). CNS injury leads to the development of a range of reactive phenotypes in astrocytes whose molecular determinants are poorly understood. Finding ways to modulate astrocytic injury responses and leverage a pro-recovery phenotype holds promise in treating CNS injury. Recently, it has been demonstrated that ablation of astrocytic transglutaminase 2 (TG2) modulates the phenotype of reactive astrocytes in a way that improves neuronal injury outcomes both in vitro and in vivo. In an in vivo mouse model, pharmacological inhibition of TG2 with the irreversible inhibitor VA4 phenocopies the neurosupportive effects of TG2 deletion in astrocytes. In this study, we provide insights into the mechanisms by which TG2 deletion or inhibition result in a more neurosupportive astrocytic phenotype. Using a neuron-astrocyte co-culture model, we show that VA4 treatment improves the ability of astrocytes to support neurite outgrowth on an injury-relevant matrix. To better understand how pharmacologically altering TG2 affects its ability to regulate reactive astrocyte phenotypes, we assessed how VA4 inhibition impacts TG2s interaction with Zbtb7a, a transcription factor we have previously identified as a functionally relevant TG2 nuclear interactor. The results of these studies demonstrate that VA4 significantly decreases the interaction of TG2 and Zbtb7a. TG2s interactions with Zbtb7a, as well as a wide range of other transcription factors and chromatin regulatory proteins, suggest that TG2 may act as an epigenetic regulator to modulate gene expression. To begin to understand if TG2-mediated epigenetic modification may impact astrocytic phenotypes in our models, we interrogated the effect of TG2 deletion and VA4 treatment on histone acetylation and found significantly greater acetylation in both experimental groups. Consistent with these findings, previous RNA-sequencing and our present proteomic analysis also supported a predominant transcriptionally suppressive role of TG2 in astrocytes. Our proteomic data additionally unveiled pronounced changes in lipid and antioxidant metabolism in astrocytes with TG2 deletion or inhibition, which likely contribute to the enhanced neurosupportive function of these astrocytes.

Epigenetic insights into creep-feeding: methylation profiling of Longissimus thoracis muscle at weaning in crossbred cattle

IntroductionThis study investigated the impact of creep-feeding supplementation on the genome methylation of the Longissimus thoracis (LT) muscle in crossbred beef cattle (Bos taurus × Bos indicus).MethodsThe experiment involved 48 uncastrated F1 Angus-Nellore males (half-siblings), which were divided into two groups: NCF – no creep-feeding (n = 24) and CF – creep-feeding (n = 24). After weaning at 210 days, all animals were feedlot finished for 180 days under identical conditions. LT muscle biopsies were collected at weaning for genomic DNA methylation analysis by reduced representation bisulfite sequencing (RRBS).Results and discussionThe groups differed significantly (CF &amp;gt; NCF: p &amp;lt; 0.05) to weaning weight (243.57±5.70 vs. 228.92±5.07kg), backfat thickness (12.96±0.86 vs. 10.61±0.42mm), LT muscle marbling score (366.11±12.39 vs. 321.50±13.65), and LT intramuscular fat content (5.80±0.23 vs. 4.95±0.20%). The weights at the beginning of the experiment and at slaughter (390 days) did not differ significantly. Mean methylation levels were higher in CF with 0.18% more CpG, 0.04% CHG, and 0.03% CHH. We identified 974 regions with differential methylation (DMRs: &amp;gt; 25% and q &amp;lt; 0.05), which overlapped with 241 differentially methylated genes (DMGs). Among these genes, 108 were hypermethylated and 133 were hypomethylated in CF group. Notably, 39 of these DMGs were previously identified as differentially expressed genes (DEGs: log2 fold change [0.5]) in the same animal groups. Over-representation analysis highlighted epigenetic regulations related to muscle growth, PPAR signaling, adipogenesis, insulin response, and lipid metabolism. Key DMGs/DEGs included: ACAA1, SORBS1, SMAD3, TRIM63, PRKCA, DNMT3A, RUNX1, NRG3, and SLC2A8. These epigenetic changes improved the performance of supplemented animals up to weaning and enhanced meat quality traits, particularly higher intramuscular fat. The results provided insights into the intricate interplay between nutrition, epigenetics, gene expression and phenotypes in beef cattle production.

Genome-wide analysis of non-coding RNA reveals the role of a novel miR319c for tuber dormancy release process in potato

Abstract Tuber dormancy and sprouting are significant for potato cultivation, storage, and processing. Although the substantial role of miRNAs in some biological processes has been recognized, the critical role of miRNA in breaking potato tuber dormancy is not well understood to date. In this investigation, we expand research on miRNA-mediated gene regulation in tuber dormancy release. In this work, 204 known and 192 novel miRNAs were identified. 136 differentially expressed miRNAs (DE-miRNAs) were also screened out, of which 56 DE-miRNAs were regulated by temperature during tuber dormancy release. Additionally, degradome sequencing revealed that 821 target genes for 202 miRNAs were discovered. Among them, 63 target genes and 48 miRNAs were predicted to be involved in plant hormone signaling pathways. This study used degradome sequencing, tobacco co-transformation system, and GUS staining technology to confirm that stu-miR319c can target StTCP26 and StTCP27 and effectively suppress their expression. The transgenic approach exhibited that stu-miR319c overexpressed tubers sprouted in advance, while silent expression of stu-miR319c showed delayed sprouting. Treatment of wild-type tubers with exogenous MeJA revealed that 1 mg/L MeJA significantly broke dormancy and enhanced potato sprouting ability. Furthermore, transgenic tubers revealed variance in JA content and relative expression of genes associated with JA synthesis pathway, including StAOC, StLOX2, and StLOX4, suggesting that the miR319c may participate in the JA pathway to regulate tuber dormancy release. In summary, our research offers evidence that miRNA regulates potato dormancy release and supports the idea that stu-miR319c is a unique epigenetic regulator for dormancy-sprouting transition in potatoes.

H4K20me3-Mediated Repression of Inflammatory Genes is a Characteristic and Targetable Vulnerability of Persister Cancer Cells.

Anti-cancer therapies can induce cellular senescence, which is highly stable, or drug-tolerant persistence, which is efficiently reversed upon therapy termination. While approaches to target senescent cells have been extensively studied, further understanding of the processes regulating persistence is needed to develop treatment strategies to suppress persister cell survival. Here, we used mTOR/PI3K inhibition to develop and characterize a model of persistence-associated arrest in human cancer cells of various origins. Persister and senescent cancer cells shared an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells lacked other features of senescence, such as loss of lamin B1, senescence-associated β-galactosidase activity, upregulation of MHC-I, and an inflammatory and secretory phenotype (SASP). Genome-wide CRISPR/Cas9 screening for genes required for the survival of persister cells revealed that they are hypersensitive to the inhibition of one-carbon (1C) metabolism, which was validated by the pharmacological inhibition of SHMT, a key enzyme that feeds methyl groups from serine into 1C metabolism. Connecting 1C metabolism with the epigenetic regulation of transcription, the repressive heterochromatic mark H4K20me3 was enriched at the promoters of SASP and interferon response genes in persister cells, while it was absent in proliferative or senescent cells. Moreover, persister cells overexpressed the H4K20 methyltransferases KMT5B/C, and their downregulation unleashed inflammatory programs and compromised the survival of persister cells. In summary, this study defined distinctive features of persister cancer cells, identified actionable vulnerabilities, and provided mechanistic insight into their low inflammatory activity.