Broad H3K4me3 domains: Maintaining cellular identity and their implication in super-enhancer hijacking.

The human and mouse genomes are complex from a genomic standpoint. Each cell has the same genomic sequence, yet a wide array of cell types exists due to the presence of a plethora of regulatory elements in the non-coding genome. Recent advances in epigenomic profiling have uncovered non-coding gene proximal promoters and distal enhancers of transcription genome-wide. Extension of promoter-associated H3K4me3 histone mark across the gene body, known as a broad H3K4me3 domain (H3K4me3-BD), is a signature of constitutive expression of cell-type-specific regulation and of tumour suppressor genes in healthy cells. Recently, it has been discovered that the presence of H3K4me3-BDs over oncogenes is a cancer-specific feature associated with their dysregulated gene expression and tumourigenesis. Moreover, it has been shown that the hijacking of clusters of enhancers, known as super-enhancers (SE), by proto-oncogenes results in the presence of H3K4me3-BDs over the gene body. Therefore, H3K4me3-BDs and SE crosstalk in healthy and cancer cells therefore represents an important mechanism to identify future treatments for patients with SE driven cancers.

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis.

Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1-/- mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.

Two-stage thermal pyrolysis of plastic solid waste: Set-up and operative conditions investigation for gaseous fuel production.

In response to the escalating global challenge of mounting plastic waste and the imperative to adopt more sustainable practices for resource utilization, our study focuses on the utilization of plastic solid waste (PSW) through a two-stage thermal pyrolysis process. This aims to demonstrate its potential as a high-performance alternative to existing two-stage catalytic pyrolysis methods. The experimentation involved processing real scrap PSW material in a lab-scale batch set-up, emphasizing optimizing residence time in the cracking reactor to maximize gas yield and its lower heating value (LHV). The study underscores the advantages of the employed two-stage thermal pyrolysis apparatus through a comparative analysis with established set-up dedicated to maximizing gas yield. Once the operative conditions were explored, resulting pyrolysis products underwent detailed characterization to assess their suitability as a sustainable fuel source. The study also presents a practical application of the produced gaseous fuel, envisioning its combustion in an internal combustion engine (ICE), known for its flexibility regarding fuel properties. This application is demonstrated through a simulation conducted in Unisim Design©. The successful processing of real PSW material in the two-stage lab-scale experimental set-up showcased optimal gas yield achievements (>65 % w/w) with an LHV (∼41 MJ/kg), comparable to that of natural gas. This emphasizes the potential of these sustainable alternatives to replace fossil fuels, especially in the context of ICE applications. The integration of the pyrolysis plant with an ICE demonstrated promising prospects for generating electricity in the transportation sector and facilitating thermal power for heat integration in pyrolysis reactors.

HDAC1 interacts with the p50 NF-?B subunit via its nuclear localization sequence to constrain inflammatory gene expression.

The NF-?B p50 subunit is an important regulator of inflammation, with recent experimental evidence to support it also having a tumor suppressor role. Classically, p50 functions in heterodimeric form with the RelA (p65) NF-?B subunit to activate inflammatory genes. However, p50 also forms homodimers which actively repress NF-?B-dependent inflammatory gene expression and exert an important brake on the inflammatory process. This repressive activity of p50:p50 is thought to be in part mediated by an interaction with the epigenetic repressor protein Histone Deacetylase 1 (HDAC1). However, neither the interaction of p50 with HDAC1 nor the requirement of HDAC1 for the repressive activities of p50 has been well defined. Here we employed in silico prediction with in vitro assays to map sites of interaction of HDAC1 on the p50 protein. Directed mutagenesis of one such region resulted in almost complete loss of HDAC1 binding to p50. Transfected mutant p50 protein lacking the putative HDAC1 docking motif resulted in enhanced cytokine and chemokine expression when compared with cells expressing a transfected wild type p50. In addition, expression of this mutant p50 was associated with enhanced chemoattraction of neutrophils and acetylation of known inflammatory genes demonstrating the likely importance of the p50:HDAC1 interaction for controlling inflammation. These new insights provide an advance on current knowledge of the mechanisms by which NF-?B-dependent gene transcription are regulated and highlight the potential for manipulation of p50:HDAC1 interactions to bring about experimental modulation of chronic inflammation and pathologies associated with dysregulated neutrophil accumulation and activation.