Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1-anilino-3-(3,6-dibromocarbazol-9-yl) propan-2-ol) on chemically induced muscle injury. Muscle injury was induced by injecting 50 µL 1.2% barium chloride (BaCl2) into the tibialis anterior (TA) muscle in C57Bl/6J wild-type male mice. Mice were then treated with either 10 mg/kg body weight of P7C3 or Vehicle intraperitoneally for 7 days and assessed for histological, biochemical, and molecular changes. In the present study, we show that the acute BaCl2-induced TA muscle injury was robust and the P7C3-treated mice displayed a significant increase in the total number of myonuclei and blood vessels, and decreased serum CK activity compared with vehicle-treated mice. The specificity of P7C3 was evaluated using Nampt+/- mice, which did not display any significant difference in muscle repair capacity among treated groups. RNA-sequencing analysis of the injured TA muscles displayed 368 and 212 genes to be exclusively expressed in P7C3 and Veh-treated mice, respectively. There was an increase in the expression of genes involved in cellular processes, inflammatory response, angiogenesis, and muscle development in P7C3 versus Veh-treated mice. Conversely, there is a decrease in muscle structure and function, myeloid cell differentiation, glutathione, and oxidation-reduction, drug metabolism, and circadian rhythm signaling pathways. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) and reverse transcription-qPCR analyses identified increased Pax7, Myf5, MyoD, and Myogenin expression in P7C3-treated mice. Increased histone lysine (H3K) methylation and acetylation were observed in P7C3-treated mice, with significant upregulation in inflammatory markers. Moreover, P7C3 treatment significantly increased the myotube fusion index in the BaCl2-injured human skeletal muscle in vitro. P7C3 also inhibited the lipopolysaccharide-induced inflammatory response and mitochondrial membrane potential of RAW 264.7 macrophage cells. Overall, we demonstrate that P7C3 activates muscle stem cells and enhances muscle injury repair with increased angiogenesis.

As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.

Fumonisin B1 (FB1) poses a risk to animal and human health. Although the effects of FB1 on sphingolipid metabolism are well documented, there are limited studies covering the epigenetic modifications and early molecular alterations associated with carcinogenesis pathways caused by FB1 nephrotoxicity. The present study investigates the effects of FB1 on global DNA methylation, chromatin-modifying enzymes, and histone modification levels of the p16 gene in human kidney cells (HK-2) after 24 h exposure. An increase (2.23-fold) in the levels of 5-methylcytosine (5-mC) at 100 µmol/L was observed, a change independent from the decrease in gene expression levels of DNA methyltransferase 1 (DNMT1) at 50 and 100 µmol/L; however, DNMT3a and DNMT3b were significantly upregulated at 100 µmol/L of FB1. Dose-dependent downregulation of chromatin-modifying genes was observed after FB1 exposure. In addition, chromatin immunoprecipitation results showed that 10 µmol/L of FB1 induced a significant decrease in H3K9ac, H3K9me3 and H3K27me3 modifications of p16, while 100 µmol/L of FB1 caused a significant increase in H3K27me3 levels of p16. Taken together, the results suggest that epigenetic mechanisms might play a role in FB1 carcinogenesis through DNA methylation, and histone and chromatin modifications.

Embryonic expression of DNMT3B is critical for establishing de novo DNA methylation. This study uncovers the mechanism through which the promoter-associated long non-coding RNA (lncRNA) Dnmt3bas controls the induction and alternative splicing of Dnmt3b during embryonic stem cell (ESC) differentiation. Dnmt3bas recruits the PRC2 (polycomb repressive complex 2) at cis-regulatory elements of the Dnmt3b gene expressed at a basal level. Correspondingly, Dnmt3bas knockdown enhances Dnmt3b transcriptional induction, whereas overexpression of Dnmt3bas dampens it. Dnmt3b induction coincides with exon inclusion, switching the predominant isoform from the inactive Dnmt3b6 to the active Dnmt3b1. Intriguingly, overexpressing Dnmt3bas further enhances the Dnmt3b1:Dnmt3b6 ratio, attributed to its interaction with hnRNPL (heterogeneous nuclear ribonucleoprotein L), a splicing factor that promotes exon inclusion. Our data suggest that Dnmt3bas coordinates alternative splicing and transcriptional induction of Dnmt3b by facilitating the hnRNPL and RNA polymerase II (RNA Pol II) interaction at the Dnmt3b promoter. This dual mechanism precisely regulates the expression of catalytically active DNMT3B, ensuring fidelity and specificity of de novo DNA methylation.

For over four decades, mass spectrometry-based methods have provided a wealth of information relevant to various challenges in the field of cancers research. These challenges included identification and validation of novel biomarkers for various diseases, in particular for various forms of cancer. These biomarkers serve various objectives including monitoring patient response to the various forms of therapy, differentiating subgroups of the same type of cancer, and providing proteomic data to complement datasets generated by genomic, epigenetic, and transcriptomic methods. The same proteomic data can be used to provide prognostic information and could guide scientists and medics to new and innovative targeted therapies The past decade has seen a rapid emergence of epigenetics as a major contributor to carcinogenesis. This development has given a fresh momentum to MS-based proteomics, which demonstrated to be an unrivalled tool for the analyses of protein post-translational modifications associated with chromatin modifications. In particular, high-resolution mass spectrometry has been recently used for systematic quantification of chromatin modifications. Data generated by this approach are central in the search for new therapies for various forms of cancer and will help in attempts to decipher antitumor drug resistance. To appreciate the contribution of mass spectrometry-based proteomics to biomarkers discovery and to our understanding of mechanisms behind the initiation and progression of various forms of cancer, a number of recent investigations are discussed. These investigations also include results provided by two-dimensional gel electrophoresis combined with mass spectrometry.

H2A.Z-containing nucleosomes have been found to function in various developmental programs in Arabidopsis (e.g., floral transition, warm ambient temperature, and drought stress responses). The SWI2/SNF2-Related 1 Chromatin Remodeling (SWR1) complex is known to control the deposition of H2A.Z, and it has been unraveled that ACTIN-RELATED PROTEIN 6 (ARP6) is one component of this SWR1 complex. Previous studies showed that the arp6 mutant exhibited some distinguished phenotypes such as early flowering, leaf serration, elongated hypocotyl, and reduced seed germination rate in response to osmotic stress. In this study, we aimed to investigate the changes of arp6 mutant when the plants were grown in salt stress condition. The phenotypic observation showed that the arp6 mutant was more sensitive to salt stress than the wild type. Upon salt stress condition, this mutant exhibited attenuated root phenotypes such as shorter primary root length and fewer lateral root numbers. The transcript levels of stress-responsive genes, ABA INSENSITIVE 1 (ABI1) and ABI2, were found to be impaired in the arp6 mutant in comparison with wild-type plants in response to salt stress. In addition, a meta-analysis of published data indicated a number of genes involved in auxin response were induced in arp6 mutant grown in non-stress condition. These imply that the loss of H2A.Z balance (in arp6 mutant) may lead to change stress and auxin responses resulting in alternative root morphogenesis upon both normal and salinity stress conditions.

Forest trees are complex perennial organisms that are adapted to the local environment in the results of prevailing climate conditions in population history. Because they lead a sedentary lifestyle, plants are exposed to various environmental stimuli, such as changes which can lead to the rapid adjustment or failure of their defence mechanisms. As forests play a key role in environment homeostasis and are the source of many products, it is crucial to estimate the role of forest trees\' plasticity mechanisms in the face of the climate change. Fast epigenetic adjustment is the basis for surviving climate fluctuations, however the question is whether this mechanism will be also efficient if climate fluctuations increase. Epigenetic modifications enable rapid reactions to the inducing stimulus by establishing chromatin patterns and manipulating gene expression without affecting the DNA itself. This work aimed to gather information about the epigenetic mechanisms of tree responses to changing environmental conditions, in order to summarise what is known so far and emphasize the significance of the discussed issue. Applying this knowledge in the future to study the interactions between climate change and gene regulation at the levels of plant development could generate answers to questions about the limitations of plasticity of plant adaptation to changing environment. We still know very little about how organisms, especially trees, cope with climate change and we believe that this overview will encourage researchers to fill this gap in the knowledge, and that results will be applied in improving defensive capacity of this ecologically and economically important species.

Histone posttranslational modifications shape the chromatin landscape of the plant genome and affect gene expression in response to developmental and environmental cues. To date, the role of histone modifications in regulating plant responses to environmental nutrient availability, especially in agriculturally important species, remains largely unknown. We describe the functions of two histone lysine methyltransferases, SET Domain Group 33 (SDG33) and SDG34, in mediating nitrogen (N) responses of shoots and roots in tomato. By comparing the transcriptomes of CRISPR edited tomato lines sdg33 and sdg34 with wild-type plants under N-supplied and N-starved conditions, we uncovered that SDG33 and SDG34 regulate overlapping yet distinct downstream gene targets. In response to N level changes, both SDG33 and SDG34 mediate gene regulation in an organ-specific manner: in roots, SDG33 and SDG34 regulate a gene network including Nitrate Transporter 1.1 (NRT1.1) and Small Auxin Up-regulated RNA (SAUR) genes. In agreement with this, mutations in sdg33 or sdg34 abolish the root growth response triggered by an N-supply; In shoots, SDG33 and SDG34 affect the expression of photosynthesis genes and photosynthetic parameters in response to N. Our analysis thus revealed that SDG33 and SDG34 regulate N-responsive gene expression and physiological changes in an organ-specific manner, thus presenting previously unknown candidate genes as targets for selection and engineering to improve N uptake and usage in crop plants.

Hypoxia is defined as a cellular stress condition caused by a decrease in oxygen below physiologically normal levels. Cells in the core of a rapidly growing solid tumor are faced with the challenge of inadequate supply of oxygen through the blood, owing to improper vasculature inside the tumor. This hypoxic microenvironment inside the tumor initiates a gene expression program that alters numerous signaling pathways, allowing the cancer cell to eventually evade adverse conditions and attain a more aggressive phenotype. A multitude of studies covering diverse aspects of gene regulation has tried to uncover the mechanisms involved in hypoxia-induced tumorigenesis. The role of epigenetics in executing widespread and dynamic changes in gene expression under hypoxia has been gaining an increasing amount of support in recent years. This chapter discusses, in detail, various epigenetic mechanisms driving the cellular response to hypoxia in cancer.

Modern epigenetics emerged about 40 years ago. Since then, the field has rapidly grown. Unfortunately, this development has been accompanied by certain misconceptions and methodological shortcomings. A profound misconception is that chromatin modifications are a distinct layer of gene regulation that is directly responsive to the environment and potentially heritable between generations. This view ignores the fact that environmental factors affect gene expression mainly through signaling cascades and the activation or repression of transcription factors, which recruit chromatin regulators. The epigenome is mainly shaped by the DNA sequence and by transcription. Methodological shortcomings include the insufficient consideration of genetic variation and cell mixture distribution. Mis- and overinterpretation of epigenetic data foster genetic denialism (\"We can control our genes\") and epigenetic determinism (\"You are what your parents ate\"). These erroneous beliefs can be overcome by using precise definitions, by raising the awareness about methodological pitfalls and by returning to the basic facts in molecular and cellular biology.