Precision (individualized) medicine relies on the molecular profiling of tumors\' dysregulated characteristics (genomic, epigenetic, transcriptomic) to identify the reliance on key pathways (including genome stability and epigenetic gene regulation) for viability or growth, and then utilises targeted therapeutics to disrupt these survival-dependent pathways. Non-mutational epigenetic changes alter cells\' transcriptional profile and are a key feature found in many tumors. In contrast to genetic mutations, epigenetic changes are reversable, and restoring a normal epigenetic profile can inhibit tumor growth and progression. Lysine acetyltransferases (KATs or HATs) protect genome stability and integrity, and Tip60 is an essential acetyltransferase due to its roles as an epigenetic and transcriptional regulator, and as master regulator of the DNA double-strand break response. Tip60 is commonly downregulated and mislocalized in many cancers, and the roles that mislocalized Tip60 plays in cancer are not well understood. Here we categorize and discuss Tip60-regulated genes, evaluate Tip60-interacting proteins based on cellular localization, and explore the therapeutic potential of Tip60-targeting compounds as epigenetic inhibitors. Understanding the multiple roles Tip60 plays in tumorigenesis will improve our understanding of tumor progression and will inform therapeutic options, including informing potential combinatorial regimes with current chemotherapeutics, leading to improvements in patient outcomes.

Diseases caused by trypanosomatid parasites remain a significant unmet medical need for millions of people globally. Trypanosomatid parasites such as Trypanosoma cruzi and subspecies of Trypanosoma brucei cause Chagas disease and human African trypanosomiasis (HAT), respectively. Although efforts to find novel treatments have been successful for HAT, Chagas disease is still treated with decades-old therapies that suffer from long treatment durations and severe safety concerns. We recently described the identification and characterization of the cyanotriazole compound class that kills trypanosomes, in vitro and in vivo, by selective inhibition of the trypanosome nuclear topoisomerase II enzyme. To evaluate whether inhibition of the topoisomerase II enzyme led to parasite death due to lethal double-strand DNA breaks, we developed assays for detecting DNA damage in both intracellular amastigotes of T. cruzi and bloodstream-form T. brucei by using the canonical DNA damage marker γH2A. Herein, this article describes the protocols for detecting DNA damage using an immunofluorescence assessment of γH2A by microscopy in trypanosome parasites. Key features • Immunofluorescence-based assay to detect the γH2A response in T. brucei and T. cruzi parasites. • Robust DNA damage pathway-based cellular assays to evaluate topoisomerase II poisons\' ability to cause DNA damage. • A 384-well plate-based T. cruzi protocol allows high-resolution and high-throughput evaluation of compounds that cause DNA damage by measuring γH2A in intracellular parasites. • This assay could be modifiable for evaluation of DNA damage responses in various intracellular and extracellular eukaryotic pathogens.

Epigenetic mechanisms control and regulate normal chromatin structure and gene expression patterns, with epigenetic dysregulation observed in many different cancer types. Importantly, epigenetic modifications are reversible, offering the potential to silence oncogenes and reactivate tumor suppressors. Small molecule drugs manipulating these epigenetic mechanisms are at the leading edge of new therapeutic options for cancer treatment. The clinical use of histone deacetyltransferases inhibitors (HDACi) demonstrates the effectiveness of targeting epigenetic mechanisms for cancer treatment. Notably, the development of new classes of inhibitors, including lysine acetyltransferase inhibitors (KATi), are the future of epigenetic-based therapeutics. We outline the progress of current classes of small molecule epigenetic drugs for use against cancer (preclinical and clinical) and highlight the potential market growth in epigenetic-based therapeutics.

Human adenoviruses (HAdV) belong to a small DNA tumor virus family that continues as valuable models in understanding the viral strategies of usurping cell growth regulation. A number of HAdV type 2/5 early viral gene products interact with a variety of cellular proteins to build a conducive environment that promotes viral replication. Here we show that HBO1 (Histone Acetyltransferase Binding to ORC1), a member of the MYST histone acetyltransferase (HAT) complex (also known as KAT7 and MYST2) that acetylates most of the histone H3 lysine 14, is essential for HAdV5 growth. HBO1/MYST2/KAT7 HAT complexes are critical for a variety of cellular processes including control of cell proliferation. In HBO1 downregulated human cells, HAdV5 infection results in reduced expression of E1A and other viral early genes, virus growth is also reduced significantly. Importantly, HBO1 downregulation reduced H3 lysine 14 acetylation at viral promoters during productive infection, likely driving reduced viral gene expression. HBO1 was also associated with viral promoters during infection and co-localized with viral replication centers in the nuclei of infected cells. In transiently transfected cells, overexpression of E1A along with HBO1 stimulated histone acetyltransferase activity of HBO1. E1A also co-immunoprecipitated with HBO1 in transiently transfected cells. In summary, our results demonstrate that HAdV recruits the HBO1 HAT complex to aid in viral replication.

Spinal cord injury (SCI) leads to deficits of various normal functions and is difficult to return to a normal state. Histone and non-histone protein acetylation after SCI is well documented and regulates spinal cord plasticity, axonal growth, and sensory axon regeneration. However, our understanding of protein acetylation after SCI is still limited. In this review, we summarize current research on the role of acetylation of histone and non-histone proteins in regulating neuron growth and axonal regeneration in SCI. Furthermore, we discuss inhibitors and activators targeting acetylation-related enzymes, such as α-tubulin acetyltransferase 1 (αTAT1), histone deacetylase 6 (HDAC6), and sirtuin 2 (SIRT2), to provide promising opportunities for recovery from SCI. In conclusion, a comprehensive understanding of protein acetylation and deacetylation in SCI may contribute to the development of SCI treatment.

BACKGROUND: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease), including its severe clinical forms, involves complex processes at all levels of biological organization. This study examined the potential link between the liver microbiome profile and epigenetic factors.
METHODS: Liver microbial DNA composition was analysed using high throughput 16S rRNA gene sequencing in 116 individuals, with 55% being female, across the spectrum of liver disease severity. Total activity of histone deacetylases (HDACs) and acetyltransferases (HATs) was assayed in nuclear extracts from fresh liver samples. In addition, we measured the global 5-hydroxymethylcytosine (5-hmC) levels of liver DNA.
RESULTS: Patients with MASLD showed a 2.07-fold increase (p = 0.013) in liver total HAT activity. Moreover, a correlation was observed between liver total HAT activity and the score for histological steatosis (Spearman\'s R = 0.60, p = 1.0E-3) and disease severity (R = 0.40, p = 2.0E-2). Liver HAT and HDAC activities also showed associations with the abundance of several liver bacterial DNAs. Additionally, liver global levels of 5-hmC showed negative correlation with the read number of Bacteroidetes (R = -0.62, p = 9.3E-4) and Gammaproteobacteria (R = -0.43, p = 3.2E-2), while it was positively correlated with the abundance of Acidobacteria (R = 0.42, p = 4.1E-2) and Actinobacteria (R = 0.47, p = 1.8E-2).
CONCLUSIONS: The host liver epigenome, including the activity of enzymes involved in maintaining the balance between protein acetylation and deacetylation and the global DNA hydroxy-methylation status, may be the target of microbial signals.
BACKGROUND: Agencia Nacional de Promoción Científica y Tecnológica, FonCyT.

Human infections by trypanosomatids are widely distributed and prevalent in the tropical and subtropical regions. Diseases caused by Trypanosoma and Leishmania have variable clinical outcomes, ranging from self-healing to fatality, and are considered Neglected Tropical Diseases (NTD). In addition, animal trypanosomiases have a significant impact on animal health and production, apart from their potential role as reservoirs in zoonotic species. Control of these infections is progressing and, in some cases (such as human African trypanomiasis (HAT)), significant reductions have been achieved. In the absence of effective vaccination, chemotherapy is the most used control method. Unfortunately, the therapeutic arsenal is scarce, old, and of variable efficacy, and reports of resistance to most antiparasitic agents have been published. New drugs, formulations, or combinations are needed to successfully limit the spread and severity of these diseases within a One Health framework. In this Special Issue, contributions regarding the identification and validation of drug targets, underlying mechanisms of action and resistance, and potential new molecules are presented. These research contributions are complemented by an update revision of the current chemotherapy against African Trypanosoma species, and a critical review of the shortcomings of the prevailing model of drug discovery and development.

Tryptase has proven to be a very useful and specific marker to demonstrate mast cell activation and degranulation when an acute (i.e., within 4 h after the event) and baseline value (i.e., at least 24 h after the event) are compared and meet the consensus formula (i.e., an increase of 20% + 2). The upper limit of normal determined by the manufacturer is 11.4 ng/mL; however, this boundary has been the subject of debate. According to ECNM and AIM experts, the normal range of baseline tryptase should be 1 to 15 ng/mL. A genetic trait, hereditary alpha tryptasemia, characterized by an increased alpha coding TPSAB1 copy number is associated with a baseline value above 8 ng/mL. Elevated tryptase can also be found in chronic kidney disease, obesity, and hematological neoplasms. A tryptase > 20 ng/mL serves as a minor criterion to diagnose systemic mastocytosis and an increase in tryptase > 20% + 2 during an acute event is a required criterion in the diagnosis of mast cell activation syndrome. The goal of this review is to demonstrate the (in)significance of tryptase using some clinical vignettes and to provide a practical guide on how to manage and interpret an elevated tryptase level.

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense and rhodesiense, is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth of T. b. brucei, T. b. gambiense and T. b. rhodesiense, have excellent oral bioavailability and was effective in treating acute infection of HAT in mouse models. Based on its excellent bioavailability, compound 10 and its analogs are candidates for lead optimization and pre-clinical investigations.

Histones are subject to a diverse array of post-translational modifications. Among them, lysine acetylation is not only the most pervasive and dynamic modification but also highly consequential for regulating gene transcription. Although enzymes responsible for the addition and removal of acetyl groups were discovered almost 30 years ago, high-resolution structures of the enzymes in the context of their native complexes are only now beginning to become available, thanks to revolutionary technologies in protein structure determination and prediction. Here, we will review our current understanding of the molecular mechanisms of acetylation and deacetylation engendered by chromatin-modifying complexes, compare and contrast shared features, and discuss some of the pressing questions for future studies.