Histone Acetylation Research Articles

8759 Mild Iodine Deficiency During Pregnancy Impairs Hypothalamus-Pituitary-Thyroid Function Programing of the Adult Male Offspring

Abstract Disclosure: M. Oliveira: None. E. Tavares: None. G. Henrique: None. J. Pinto: None. C. Serrano-Nascimento: None. Introduction: Iodine plays a crucial role in the biosynthesis of thyroid hormones and is essential for proper thyroid embryonic development. While severe iodine deficiency during pregnancy and lactation has well-documented deleterious effects, the consequences of mild iodine deficiency (MID) remain not fully understood. MID during pregnancy is a reality in numerous countries, even in regions with seemingly adequate iodine supply in the diet. Previous studies have highlighted the adverse impact of MID on neurological development in offspring, but comprehensive data on thyroid function, particularly in progeny at different developmental stages, are lacking. This study aimed to investigate the repercussions of MID during pregnancy on the programming of thyroid dysfunctions during adulthood. Methods: Female CD1 mice were subjected to iodine-deficient animal chow and iodine-supplemented water, either at normal (NI; 0.2 mg/L) or mild iodine deficiency (MID; 0.8 mg/L) levels during pregnancy. Gene and protein expression in the hypothalamus, pituitary, and thyroid of adult male offspring animals (PND90) were evaluated using qPCR and Western blotting. Additionally, this study explored MID-induced programming of offspring thyroid gene expression through epigenetic mechanisms. Results: Maternal MID exposure led to increased gene and protein expression of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) in the hypothalamus and pituitary of the offspring animals. Thyroid protein and gene expression of sodium iodide symporter (NIS), TSH receptor (TSHR), thyroid peroxidase (TPO), thyroglobulin (TG), paired box 8 (PAX8), NK2 homeobox 1 (NKX2.1), and monocarboxylate transporter 8 (MCT8) were elevated in the offspring of MID-exposed animals. Epigenetic mechanisms appeared to contribute to the augmented thyroid gene expression in MID-exposed animals, with decreased DNA methyltransferase expression and reduced thyroid DNA global methylation. Additionally, histone 3 hypomethylation and increased acetylation of histones 3 and 4 were observed. Conclusion: The study suggests that MID exposure during pregnancy can be as harmful as severe iodine deficiency in programming the hypothalamus-pituitary-thyroid (HPT) axis, leading to HPT dysfunction during adult life. Consequently, our data suggest that monitoring iodine intake throughout pregnancy is crucial to prevent the occurrence of thyroid disorders in offspring during adulthood. Presentation: 6/1/2024

7080 Copy Number Variation (CNV) in Self-Limited Delayed Puberty (SLDP)

Abstract Disclosure: Y. Al-Sayed: None. M. Ishida: None. C.L. Hall: None. S. Howard: None. SLDP is where the onset of puberty is more than 2-2.5 standard deviations later than the population mean age and is often familial with strong genetic determinants. The reproductive axis is regulated by gonadotropin-releasing hormone (GnRH), which plays a crucial role in initiating puberty and maintaining fertility through its pulsatile secretion. Disruption in GnRH neuron development or hypothalamic function can lead to DP. UK Biobank data has identified negative health outcomes associated with SLDP including early menopause/andropause and cognitive and psychosocial disabilities. Consequently, there has been extensive research to investigate genes affecting the hypothalamic-pituitary-gonadal (HPG) axis that might be implicated in the pathogenesis of DP by our group and others which has identified sequence variation contributing to the aetiology of SLDP. However, factors beyond nucleotide variations, such as epigenetic changes and CNVs can also lead to pubertal timing disorders. Moreover, CNVs are seen in multiple individuals (n=92) from the Deciphering Developmental Disorders study (https://www.deciphergenomics.org) with a phenotype including DP (HP:0000823). We performed whole genome sequencing on 49 probands with SLDP and subsequently, analysed the data for CNV. The data was initially called, annotated, filtered then partitioned for classification of CNVs using a command-line tool that implements the ACMG guidelines to evaluate the pathogenicity of germline duplications and deletions. Using an unbiased candidate gene approach, we identified several deletions that affected 60 known/predicted dosage sensitive genes and combines with functional enrichment analysis; This approach revealed potential molecular pathways and biological processes involved in the pathogenesis of SLDP, including histone acetylation, and neural plate development. To refine our findings, we applied additional filters, including known HPG axis genes, GWAS loci associated with pubertal timing, decipher CNV tracks, and DP gene panels, to narrow down large number of rare predicted damaging CNVs and prioritize those with potential relevance to DP. Our study highlights the potential role of CNVs in DP and expands our understanding of the molecular pathways and biological processes involved in this condition, shedding light on the complex mechanisms underlying DP. Presentation: 6/2/2024

9205 Copy Number Variation (CNV) in Self-Limited Delayed Puberty (SLDP)

Abstract Disclosure: Y. Al-Sayed: None. M. Ishida: None. C.L. Hall: None. S.R. Howard: None. SLDP is where the onset of puberty is more than 2-2.5 standard deviations later than the population mean age and is often familial with strong genetic determinants. The reproductive axis is regulated by gonadotropin-releasing hormone (GnRH), which plays a crucial role in initiating puberty and maintaining fertility through its pulsatile secretion. Disruption in GnRH neuron development or hypothalamic function can lead to DP. UK Biobank data has identified negative health outcomes associated with SLDP including early menopause/andropause and cognitive and psychosocial disabilities. Consequently, there has been extensive research to investigate genes affecting the hypothalamic-pituitary-gonadal (HPG) axis that might be implicated in the pathogenesis of DP by our group and others which has identified sequence variation contributing to the aetiology of SLDP. However, factors beyond nucleotide variations, such as epigenetic changes and CNVs can also lead to pubertal timing disorders. Moreover, CNVs are seen in multiple individuals (n=92) from the Deciphering Developmental Disorders study (https://www.deciphergenomics.org) with a phenotype including DP (HP:0000823). We performed whole genome sequencing on 49 probands with SLDP and subsequently, analysed the data for CNV. The data was initially called, annotated, filtered then partitioned for classification of CNVs using a command-line tool that implements the ACMG guidelines to evaluate the pathogenicity of germline duplications and deletions. Using an unbiased candidate gene approach, we identified several deletions that affected 60 known/predicted dosage sensitive genes and combines with functional enrichment analysis; This approach revealed potential molecular pathways and biological processes involved in the pathogenesis of SLDP, including histone acetylation, and neural plate development. To refine our findings, we applied additional filters, including known HPG axis genes, GWAS loci associated with pubertal timing, decipher CNV tracks, and DP gene panels, to narrow down large number of rare predicted damaging CNVs and prioritize those with potential relevance to DP. Our study highlights the potential role of CNVs in DP and expands our understanding of the molecular pathways and biological processes involved in this condition, shedding light on the complex mechanisms underlying DP. Presentation: 6/2/2024

Histone Deacetylase 3 Is Involved in Maintaining Queen Hallmarks of a Termite.

The role of epigenetics in regulating caste polyphenism in social insects has been debated. Here, we tested the importance of histone de/acetylation processes for the maintenance of queen hallmarks like a high fecundity and a long lifespan. To this end, we performed RNA interference experiments against histone deacetylase 3 (HDAC3) in the termite Cryptotermes secundus. Fat body transcriptomes and chemical communication profiles revealed that silencing of HDAC3 leads to signals indicative of queen hallmarks. This includes fostering of queen signalling, defence against ageing and a reduction of life-shortening IIS (insulin/insulin-like growth factor signalling) and endocrine JH (juvenile hormone) signalling via Kr-h1 (Krüppel-homologue 1). These observed patterns were similar to those of a protein-enriched diet, which might imply that histone acetylation conveys nutritional effects. Strikingly, in contrast to solitary insects, reduced endocrine JH signalling had no negative effect on fecundity-related vitellogenesis in the fat bodies. This suggests an uncoupling of longevity pathways from fecundity in fat bodies, which can help explain queens' extraordinary lifespans combined with high fecundity.

Targeting CREB-binding protein (CBP) abrogates colorectal cancer stemness through epigenetic regulation of C-MYC.

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.

Roles of Histone Acetylation and Deacetylation in Root Development

Roots are usually underground plant organs, responsible for anchoring to the soil, absorbing water and nutrients, and interacting with the rhizosphere. During root development, roots respond to a variety of environmental signals, contributing to plant survival. Histone post-translational modifications play essential roles in gene expression regulation, contributing to plant responses to environmental cues. Histone acetylation is one of the most studied post-translational modifications, regulating numerous genes involved in various biological processes, including development and stress responses. Although the effect of histone acetylation on plant responses to biotic and abiotic stimuli has been extensively reviewed, no recent reviews exist focusing on root development regulation by histone acetylation. Therefore, this review brings together all the knowledge about the impact of histone acetylation on root development in several plant species, mainly focusing on Arabidopsis thaliana. Here, we summarize the role of histone acetylation and deacetylation in numerous aspects of root development, such as stem cell niche maintenance, cell division, expansion and differentiation, and developmental zone determination. We also emphasize the gaps in current knowledge and propose new perspectives for research toward deeply understanding the role of histone acetylation in root development.

Role of genetics and epigenetics in Graves' orbitopathy.

Objectives The pathogenesis of Graves' orbitopathy (GO) remains to be fully elucidated. Here we reviewed the role of genetics and epigenetics. Design We conducted a PubMed search with the following key words: Graves' orbitopathy, thyroid eye disease; or Graves' ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome and methylome analysis were performed were chosen. Results The different prevalence of GO in the two sexes as well as racial differences suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and of patient-derived orbital fibroblasts suggest a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated. Conclusions Although pathogenetic gene variants have not been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.

ACSM3 Protects Kidney Aging and Fibrosis by Cellular Senescence via Histone Acetylation

ACSM3 Protects Kidney Aging and Fibrosis by Cellular Senescence via Histone Acetylation

Silibinin, a commonly used therapeutic agent for non-alcohol fatty liver disease, functions through upregulating intestinal expression of fibroblast growth factor 15/19.

Silibinin is used to treat non-alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action. NAFLD mice model was established by feeding them with a high-fat diet (HFD). Liver pathological were examined using H&E and oil red O staining. Tissue distribution of silibinin was detected by LC-MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP-qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno-associated virus 9-short hairpin-fibroblast growth factor (FGF)-15 and -farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF-15 and FXR. Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf-15 was selectively up-regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf-15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF-15/19. Oral silibinin selectively promotes expression of FGF-15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF-15/19 enters into circulation to exert anti-NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.

Proteomic analysis of global protein acetylation in response to WSSV infection in a crustacean Cherax quadricarinatus

Protein acetylation, a crucial post-translational modification, plays a significant role in antiviral immunity of host and viral replication processes after infection. Our previous research showed that an acetyltransferase KAT2A significantly enhanced white spot syndrome virus (WSSV) replication in hematopoietic tissue (Hpt) cells from Cherax quadricarinatus, suggesting that alterations in intracellular acetylation states affect viral infection. Nevertheless, the mechanisms by which WSSV invasion regulates intracellular protein acetylation remain unexplored. To explore the connection between protein acetylation and WSSV infection, differentially acetylated proteins (DAcPs) were identified in Hpt cells during WSSV infection by proteomic analysis. The results revealed that 25 DAcPs were identified with primarily involving in transporter activity and proton ATPase activity complex during the early stage of WSSV infection, i.e., the intracellular transport of the virions. Furthermore, that 36 DAcPs associated with chromatin assembly and acetyltransferase complex were identified in the replication stage of WSSV infection, i.e., the process of extensive viral replication. Additionally, acetylation at the K27 and K36 sites of histone H3 was strongly activated during WSSV replication; similarly, the inhibition of histone acetylation by acetyltransferase inhibiter C646 significantly suppressed WSSV replication, implying that WSSV replication requires high levels of histone acetylation, while the acetylation at the K27 and K36 sites of histone H3 probably serves as critical viral regulatory targets. This study deepens the understanding of WSSV-host interaction, and lays the groundwork for future research into the relationship between protein acetylation and viral infection in crustaceans.

Evaluation of glucocorticoid-related genes reveals GPD1 as a therapeutic target and regulator of sphingosine 1-phosphate metabolism in CRPC

Prostate cancer (PCa) is an androgen-dependent disease, with castration-resistant prostate cancer (CRPC) being an advanced stage that no longer responds to androgen deprivation therapy (ADT). Mounting evidence suggests that glucocorticoid receptors (GR) confer resistance to ADT in CRPC patients by bypassing androgen receptor (AR) blockade. GR, as a novel therapeutic target in CRPC, has attracted substantial attention worldwide. This study utilized bioinformatic analysis of publicly available CRPC single-cell data to develop a consensus glucocorticoid-related signature (Glu-sig) that can serve as an independent predictor for relapse-free survival. Our results revealed that the signature demonstrated consistent and robust performance across seven publicly accessible datasets and an internal cohort. Furthermore, our findings demonstrated that glycerol-3-phosphate dehydrogenase 1 (GPD1) in Glu-sig can significantly promote CRPC progression by mediating the cell cycle pathway. Additionally, GPD1 was shown to be regulated by GR, with the GR antagonist mifepristone enhancing the anti-tumorigenic effects of GPD1 in CRPC cells. Mechanistically, targeting GPD1 induced the production of sphingosine 1-phosphate (S1P) and enhanced histone acetylation, thereby inducing the transcription of p21 that involved in cell cycle regulation. In conclusion, Glu-sig could serve as a robust and promising tool to improve the clinical outcomes of PCa patients, and modulating the GR/GPD1 axis that promotes tumor growth may be a promising approach for delaying CRPC progression.

The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a modelfor establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.

Histone deacetylase inhibition enhances extracellular vesicles from muscle to promote osteogenesis via miR-873-3p

Regular physical activity is widely recognized for reducing the risk of various disorders, with skeletal muscles playing a key role by releasing biomolecules that benefit multiple organs and tissues. However, many individuals, particularly the elderly and those with clinical conditions, are unable to engage in physical exercise, necessitating alternative strategies to stimulate muscle cells to secrete beneficial biomolecules. Histone acetylation and deacetylation significantly influence exercise-induced gene expression, suggesting that targeting histone deacetylases (HDACs) could mimic some exercise responses. In this study, we explored the effects of the HDAC inhibitor Trichostatin A (TSA) on human skeletal muscle myoblasts (HSMMs). Our findings showed that TSA-induced hyperacetylation enhanced myotube fusion and increased the secretion of extracellular vesicles (EVs) enriched with miR-873-3p. These TSA-EVs promoted osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs) by targeting H2 calponin (CNN2). In vivo, systemic administration of TSA-EVs to osteoporosis mice resulted in significant improvements in bone mass. Moreover, TSA-EVs mimicked the osteogenic benefits of exercise-induced EVs, suggesting that HDAC inhibition can replicate exercise-induced bone health benefits. These results demonstrate the potential of TSA-induced muscle-derived EVs as a therapeutic strategy to enhance bone formation and prevent osteoporosis, particularly for individuals unable to exercise. Given the FDA-approved status of various HDAC inhibitors, this approach holds significant promise for rapid clinical translation in osteoporosis treatment.

Developmental Competence of Somatic Cell Nuclear Transfer Embryos and Interspecies ICSI Zygotes From Bovine Small Antral Follicles.

Assisted reproductive technologies (ART) play a crucial role in conserving threatened wildlife species such as Bos gaurus. ART requires a large number of mature oocytes, and small antral follicles (SAFs) in the ovary are often used to obtain abundant sources of bovine oocytes. However, oocytes from SAFs often experience difficulty completing maturation and obtaining high quality and quantity of blastocyst formation compared to fully grown oocytes. This study aimed to increase the number of high-quality mature oocytes and improve their potential for ART applications in cloned and interspecies intracytoplasmic sperm injection (ICSI) embryos by utilising L-ascorbic acid (LAA) in pre invitro maturation (pre-IVM) culture. First, oocytes isolated from SAFs were cultured with the duration of pre-IVM 0, 6, 8, 10 h and different concentrations of LAA to determine good conditions for oocyte maturation. Then, mature oocytes were assessed for their developmental competence through parthenogenesis, cloned and interspecies ICSI embryos. The results showed that 8-h pre-IVM with 50 μg/mL LAA improved the maturation rate and developmental competence of parthenogenetic and clone embryos, especially, improving the high blastocyst quality by increasing cell number and expression of histone acetylation at lysine 9 (H3K9ac). In addition, the culture process improved the nuclear reprogramming of somatic cells after nuclear transfer into mature oocytes, resulting in an increased hatching rate of cloned embryos. It also enhanced the activation and the pronuclear formation rate of Gaurus-Taurus zygotes. Overall, the established pre-IVM culture method enhanced the meiotic and developmental competence of embryos. This procedure opened hope for the preservation of endangered species and other applications.

Cpt1a Drives primed-to-naïve pluripotency transition through lipid remodeling

Metabolism has been implicated in cell fate determination, particularly through epigenetic modifications. Similarly, lipid remodeling also plays a role in regulating cell fate. Here, we present comprehensive lipidomics analysis during BMP4-driven primed to naive pluripotency transition or BiPNT and demonstrate that lipid remodeling plays an essential role. We further identify Cpt1a as a rate-limiting factor in BiPNT, driving lipid remodeling and metabolic reprogramming while simultaneously increasing intracellular acetyl-CoA levels and enhancing H3K27ac at chromatin open sites. Perturbation of BiPNT by histone acetylation inhibitors suppresses lipid remodeling and pluripotency transition. Together, our study suggests that lipid remodeling promotes pluripotency transitions and further regulates cell fate decisions, implicating Cpt1a as a critical regulator between primed-naive cell fate control.

RPS6KA1 is a histone acetylation-related oncoprotein in acute myeloid leukemia which is targeted by afzelin

BackgroundHistone acetylation plays a critical role in the progression of acute myeloid leukemia (AML). This study aimed to explore the prognostic significance and biological implications of histone acetylation-related genes in AML and to identify potential oncoproteins and therapeutic compounds.MethodsGenes associated with AML and histone acetylation were identified using the TCGA-LAML and IMEx Interactome databases. A histone acetylation-related risk model was developed using the least absolute shrinkage and selection operator method. The prognostic value of the model was evaluated through Kaplan-Meier survival analysis, time-dependent receiver operating characteristic curve, univariate and multivariate Cox regression, and nomogram calibration. Key genes were identified using random forest, support vector machine, and multivariate Cox analysis. Molecular docking was employed to assess the binding affinity between ribosomal protein S6 kinase A1 (RPS6KA1) and potential compounds. Furthermore, the effects of RPS6KA1 and afzelin on the malignant behaviors and downstream pathways of AML cells were validated through in vitro experiments.ResultsA risk model composed of 6 genes, including HDAC6, CREB3, KLF13, GOLGA2, RPS6KA1 and ZMIZ2, was established, demonstrating strong prognostic predictive capability. Among these, RPS6KA1 emerged as a key risk factor linked to histone acetylation status in AML. Elevated RPS6KA1 expression was observed in AML samples and was associated with poor prognosis. RPS6KA1 knockdown suppressed AML cell proliferation, migration, and invasion, induced G0/G1 phase arrest, and promoted apoptosis. Additionally, RPS6KA1 was identified as a potential target for afzelin, which exhibited anti-AML activity by inactivating RPS6KA1.ConclusionHistone acetylation status is closely associated with AML patient prognosis. RPS6KA1 acts as an oncoprotein in AML, facilitating disease progression. Afzelin may represent a novel therapeutic agent for AML by targeting RPS6KA1, which requires validation by clinical trials.

Histone-modifying enzymes and gastric cancer: Search for potential biomarkers and therapeutic targets based on Mendelian randomization

Gastric cancer, a common and severe malignancy, is associated with unfavorable outcomes and limited therapeutic options. The exploration of the potential link between plasma histone-modifying enzymes and gastric cancer through Mendelian randomization (MR) analysis offers an opportunity to identify new therapeutic targets and biomarkers. In this study, data on plasma histone-modifying enzymes were obtained from the International Working Unit Open genome-wide association studies project, and summary statistics of gastric cancer from the FinnGen study were analyzed. Forward and inverse MR were performed to determine the causal relationship between plasma histone-modifying enzymes and gastric cancer. The principal methodology for MR is the inverse variance weighted (IVW) method. Additionally, a sensitivity analysis was performed to determine the robustness of the findings. Finally, bioinformatics was used for the preliminary functional analysis. Our forward MR analysis revealed that the plasma Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L) was positively associated with gastric cancer risk, and the histone-lysine N-methyltransferase SETMAR (SETMAR) was negatively associated. Inverse MR analysis revealed that gastric cancer incidence was negatively correlated with the expression of plasma histone acetyltransferase KAT6A (KAT6A). These findings were consistent across different statistical methods and were deemed unlikely to have been distorted by horizontal pleiotropy. Furthermore, bioinformatics analysis indicated that ASH2L, SETMAR, and KAT6A are differentially expressed in various tumors and are significantly correlated with both the prognosis of gastric cancer and the infiltration of various immune cells. Thus, plasma histone-modifying enzymes may be causally linked to gastric cancer, and ASH2L, SETMAR, and KAT6A could play crucial roles as biomarkers and therapeutic targets in managing gastric cancer.

Sodium octanoate mediates GPR84-dependent and independent protection against sepsis-induced myocardial dysfunction

IntroductionThis study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. MethodsMale mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. ResultsSO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. ConclusionOur study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD.

DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming.

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.

The involvement of HDAC3 in the pathogenesis of lung injury and pulmonary fibrosis.

Acute lung injury (ALI) and its severe counterpart, acute respiratory distress syndrome (ARDS), are critical respiratory conditions with high mortality rates due primarily to acute and intense pulmonary inflammation. Despite significant research advances, effective pharmacological treatments for ALI and ARDS remain unavailable, highlighting an urgent need for therapeutic innovation. Notably, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the irreversible progression of fibrosis, which is initiated by repeated damage to the alveolar epithelium and leads to excessive extracellular matrix deposition. This condition is further complicated by dysregulated tissue repair and fibroblast dysfunction, exacerbating tissue remodeling processes and promoting progression to terminal pulmonary fibrosis. Similar to that noted for ALI and ARDS, treatment options for IPF are currently limited, with no specific drug therapy providing a cure. Histone deacetylase 3 (HDAC3), a notable member of the HDAC family with four splice variants (HD3α, -β, -γ, and -δ), plays multiple roles. HDAC3 regulates gene transcription through histone acetylation and adjusts nonhistone proteins posttranslationally, affecting certain mitochondrial and cytoplasmic proteins. Given its unique structure, HDAC3 impacts various physiological processes, such as inflammation, apoptosis, mitochondrial homeostasis, and macrophage polarization. This article explores the intricate role of HDAC3 in ALI/ARDS and IPF and evaluates its therapeutic potential the treatment of these severe pulmonary conditions.