Non-histone Proteins Research Articles

Targeting histone deacetylase in cardiac diseases.

Histone deacetylases (HDAC) catalyze the removal of acetylation modifications on histones and non-histone proteins, which regulates gene expression and other cellular processes. HDAC inhibitors (HDACi), approved anti-cancer agents, emerge as a potential new therapy for heart diseases. Cardioprotective effects of HDACi are observed in many preclinical animal models of heart diseases. Genetic mouse models have been developed to understand the role of each HDAC in cardiac functions. Some of the findings are controversial. Here, we provide an overview of how HDACi and HDAC impact cardiac functions under physiological or pathological conditions. We focus on in vivo studies of zinc-dependent classical HDACs, emphasizing disease conditions involving cardiac hypertrophy, myocardial infarction (MI), ischemic reperfusion (I/R) injury, and heart failure. In particular, we review how non-biased omics studies can help our understanding of the mechanisms underlying the cardiac effects of HDACi and HDAC.

Role and Mechanism of Lactylation in Cancer

Post translational modifications (PTMs) can change the properties of a protein by covalent addition of functional groups to one or more amino acids, and influence almost all aspects of normal cell biology and pathogenesis. Lactylation is a novel identified PTM, and has been found in both histone and non-histone proteins. Since associated with the end product of glycolysis-- lactate, lactylation modification could provide a new perspective for understanding the relationship between metabolic reprogramming and epigenetic modifications. Accumulated evidences suggest that lactylation play important roles in tumor progression and links to poor prognosis in clinical studies. Histone lactylation can affect gene expression in tumor cells and immunological cells, further promoting tumor progression and immune suppression. Lactylation on non-histone proteins can also regulate tumor progression and drug resistance. In this review, we aimed to summarize the roles of lactylation in cancer progression, microenvironment interactions and immune suppression, try to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy. .

Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription

In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.

Identification of molecular determinants of gene-specific bursting patterns by high-throughput imaging screens.

Stochastic transcriptional bursting is a universal property of active genes. While different genes exhibit distinct bursting patterns, the molecular mechanisms for gene-specific stochastic bursting are largely unknown. We have developed and applied a high-throughput-imaging based screening strategy to identify cellular factors and molecular mechanisms that determine the bursting behavior of human genes. Focusing on epigenetic regulators, we find that protein acetylation is a strong acute modulator of burst frequency, burst size and heterogeneity of bursting. Acetylation globally affects the Off-time of genes but has gene-specific effects on the On-time. Yet, these effects are not strongly linked to promoter acetylation, which do not correlate with bursting properties, and forced promoter acetylation has variable effects on bursting. Instead, we demonstrate acetylation of the Integrator complex as a key determinant of gene bursting. Specifically, we find that elevated Integrator acetylation decreases bursting frequency. Taken together our results suggest a prominent role of non-histone proteins in determining gene bursting properties, and they identify histone-independent acetylation of a transcription cofactor as an allosteric modulator of bursting via a far-downstream bursting checkpoint.

Chemical Proteomic Profiling of Protein Dopaminylation in Colorectal Cancer Cells.

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid of H3 (i.e., glutamine) and dopamine. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of its regulator, transglutaminase 2 (TGM2), in colon cancer cells. Due to the enzyme promiscuity of TGM2, nonhistone proteins have also been identified as dopaminylation targets; however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of dopaminylation sites were identified and attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that targeting these pathways may become a promising anticancer strategy.

The clinical significance of PRMT8 expression in esophageal squamous cell carcinoma and the influence on prognosis.

e16066 Background: Protein arginine methyltransferase 8 (PRMT8), a member of protein arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical post-translational modications (PTMs). Esophageal squamous cell carcinoma (ESCC) is the third most common cancer type of the gastrointestinal tract with poor prognosis. Abnormal arginine methylation modifications are closely associated with the development of ESCC and can exert oncogenic effects by regulating a variety of cellular processes. However, the expression of PRMT8 in ESCC and its influence on prognosis is currently unknown. Methods: After passing the application and obtaining the approval of the hospital ethics review committee and obtaining the informed consent of all patients and their families, we collected 46 cases of renal cell carcinoma diagnosed in the Fourth Hospital of Hebei Medical University from 2018 to 2023, and postoperative pathological reports of all patients confirmed to be ESCC. We followed the selected patients and obtained complete data. All the pathological specimens of the selected patients were resectioned and then subjected to immunohistochemical examination to observe the expression differences of PRMT8 in ESCC, and parallel semi-quantitative analysis. Finally, the data of the patients were statistically built. Results: PRMT8 is mainly stained on the plasma membrane of tumor cells. The difference in expression levels between ESCC and normal tissue adjacent to the cancer was statistically significant (P < 0.01). This study found that the patient’s gender, age, tumor side have no correlation with the expression levels of PRMT8 (P > 0.05), while the three indicators of tumor size, TNM stage, and lymph node metastasis are positively correlated with the expression levels of PRMT8 and the difference is statistically significant (P < 0.01). Moreover, the positive staining of PRMT1 in ESCC was significantly correlated with poor prognosis of ESCC patients. Conclusions: The expression of PRMT8 is highly expressed in ESCC and associated with aberrant clinicopathological characteristics and poor prognosis. PRMT8 is a potential target for the stratification and treatment of ESCC.

Unveiling the role of HP1α-HDAC1-STAT1 axis as a therapeutic target for HP1α-positive intrahepatic cholangiocarcinoma

BackgroundIntrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear.MethodsThe effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP).ResultsHP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents.ConclusionsHP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.

Pagetoid Bowen Disease: A Simulator of Clonal Seborrheic Keratosis, Case Report

Seborrheic keratosis (SK) and Bowen disease (BD) are different entities in dermatopathology. Differentiating between these two is important and can sometimes be a challenge for the pathologist, who may need to rely on complementary techniques. To obtain a reliable distinction, several immunohistochemistry markers have been explored such as p16 and Ki67, being positive in Bowen disease and negative in Seborrheic keratosis. Ki-67 is a non-histone protein associated with ribosomes and a well-known marker of cellular proliferation, overexpressed in Bowen disease. In addition, it has been related to a greater expression of antigens associated with the growth and differentiation of keratinocytes. P16 is a tumor suppressor gene that inhibits cyclin-dependent kinases 4 and 6. His inactivation leads to a unregulated proliferation of the cell cycle. A greater expression was found in Bowen Disease compared to Seborrheic Keratosis. Immunohistochemistry allows the distinction between entities that may be appear similar both clinically and histopathologically. This is of utmost relevance since proper treatment depends on a precise diagnosis.

Genome-Wide Identification and Expression Analysis of the High-Mobility Group B (HMGB) Gene Family in Plant Response to Abiotic Stress in Tomato.

High-mobility group B (HMGB) proteins are a class of non-histone proteins associated with eukaryotic chromatin and are known to regulate a variety of biological processes in plants. However, the functions of HMGB genes in tomato (Solanum lycopersicum) remain largely unexplored. Here, we identified 11 members of the HMGB family in tomato using BLAST. We employed genome-wide identification, gene structure analysis, domain conservation analysis, cis-acting element analysis, collinearity analysis, and qRT-PCR-based expression analysis to study these 11 genes. These genes were categorized into four groups based on their unique protein domain structures. Despite their structural diversity, all members contain the HMG-box domain, a characteristic feature of the HMG superfamily. Syntenic analysis suggested that tomato SlHMGBs have close evolutionary relationships with their homologs in other dicots. The promoter regions of SlHMGBs are enriched with numerous cis-elements related to plant growth and development, phytohormone responsiveness, and stress responsiveness. Furthermore, SlHMGB members exhibited distinct tissue-specific expression profiles, suggesting their potential roles in regulating various aspects of plant growth and development. Most SlHMGB genes respond to a variety of abiotic stresses, including salt, drought, heat, and cold. For instance, SlHMGB2 and SlHMGB4 showed positive responses to salt, drought, and cold stresses. SlHMGB1, SlHMGB3, and SlHMGB8 were involved in responses to two types of stress: SlHMGB1 responded to drought and heat, while SlHMGB3 and SlHMGB8 responded to salt and heat. SlHMGB6 and SlHMGB11 were solely regulated by drought and heat stress, respectively. Under various treatment conditions, the number of up-regulated genes significantly outnumbered the down-regulated genes, implying that the SlHMGB family may play a crucial role in mitigating abiotic stress in tomato. These findings lay a foundation for further dissecting the precise roles of SlHMGB genes.

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma.

Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.

Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia

Cancer cells tend to live in hypoxic environment characterized by enhanced glycolysis and accumulation of lactate. Intracellular lactate is shown to drive a novel type of post-translational modification (PTM), lysine lactylation (Kla). Kla has been confirmed to affect the malignant progression of tumors such as hepatocellular carcinoma (HCC) and colon cancer, whereas the global lactylomic profiling of oral squamous cell carcinoma (OSCC) is unclear. Here, the integrative lactylome and proteome analyses by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 1011 Kla sites within 532 proteins and 1197 Kla sites within 608 proteins in SCC25 cells under normoxic and hypoxic environments, respectively. Among these lactylated proteins, histones accounted for only a small fraction, suggesting the presence of Kla modification of OSCC in a large number of non-histone proteins. Notably, Kla preferred to enrich in spliceosome, ribosome and glycolysis/gluconeogenesis pathway in both normoxic and hypoxic cultures. Compared with normoxia, 589 differential proteins with 898 differentially lactylated sites were detected under hypoxia, which were mainly associated with the glycolysis/gluconeogenesis pathway by KEGG analysis. Importantly, we verified the presence of lactylation modification in the spliceosomal proteins hnRNPA1, SF3A1, hnRNPU and SLU7, as well as in glycolytic enzyme PFKP. In addition, the differential alternative splicing analysis described the divergence of pre-mRNA splicing patterns in the presence or absence of sodium lactate and at different oxygen concentrations. Finally, a negative correlation between tissue Kla levels and the prognosis of OSCC patients was revealed by immunohistochemistry. Our study is the first report to elucidate the lactylome and its biological function in OSCC, which deepens our understanding of the mechanisms underlying OSCC progression and provides a novel strategy for targeted therapy for OSCC.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure-activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson-Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

Regulation of chromatin architecture by protein binding: insights from molecular modeling.

Histone and non-histone proteins play key roles in the activation and repression of genes. In addition to experimental studies of their regulation of gene expression, molecular modeling at the nucleosome, chromatin, and chromosome levels can contribute insights into the molecular mechanisms involved. In this review, we provide an overview for protein-bound chromatin modeling, and describe how our group has integrated protein binding into genome systems across the scales, from all-atom to coarse-grained models, using explicit to implicit descriptions. We describe the associated applications to protein binding effects and biological mechanisms of genome folding and gene regulation. We end by illustrating the application of machine learning tools like AlphaFold2 to proteins relevant to chromatin systems.

A review of lactate-lactylation in malignancy: its potential in immunotherapy.

Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies of cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate have been widely observed in histone and non-histone proteins, and these modifications play a crucial role in regulating gene expression by covalently attaching lactoyl groups to lysine residues in proteins. This discovery has greatly enhanced our comprehension of lactic acid's involvement in disease pathogenesis. In this article, we provide a comprehensive review of the intricate relationship between lactate and tumor immunity, the occurrence of lactylation in malignant tumors, and the exploitation of targeted lactate-lactylation in tumor immunotherapy. Additionally, we discuss future research directions, aiming to offer novel insights that could inform the investigation, diagnosis, and treatment of related diseases.

HMGN1 loss sensitizes lung cancer cells to chemotherapy

The high mobility group nucleosome binding (HMGN) family, constitutes a large family of non-histone protein family known to bind the acidic patch of the nucleosomes with various key cellular functions. Several studies have highlighted the pivotal roles of HMGNs in the pathogenic process of various cancer types. However, the roles of HMGN family in lung adenocarcinoma (LUAD) have not been fully elucidated. Herein, integrative analyses of multiple-omics data revealed that HMGNs frequently exhibit dysregulation in LUAD. Subsequent analysis of the clinical relevance of HMGN1 demonstrated its association with poor prognosis in LUAD and its potential as a diagnostic marker to differentiate LUAD from healthy controls. Additionally, functional enrichment analysis suggested that HMGN1 was mainly involved in DNA repair. To corroborate these findings, cellular experiments were conducted, confirming HMGN1’s crucial involvement in homologous recombination repair and its potential to enhance the sensitivity of LUAD cells to standard chemotherapeutic drugs. This study proposes HMGN1 as a novel prognostic biomarker and a promising target for chemotherapy in lung adenocarcinoma.

The mechanism of high mobility group box-1 protein and its bidirectional regulation in tumors.

High-mobility group box-1 protein (HMGB1) is a nonhistone chromatin-related protein widely found in eukaryotic cells. It is involved in the transcription, replication, and repair of DNA to maintain nuclear homeostasis. It participates in cell growth, differentiation, and signal transduction. Recent studies showed that HMGB1 has a bidirectional regulatory effect on tumors by regulating TLR4/MYD88/NF-κB and RAGE/AMPK/mTOR signaling pathways. On the one hand, it is highly expressed in a variety of tumors, promoting tumor proliferation and invasion, while on the other hand, it induces autophagy and apoptosis of tumor cells and stimulates tumor-infiltrating lymphocytes to produce an anti-tumor immune response. At present, HMGB1 could be used as a target to regulate the drug resistance and prognostication in cancer. Clinical applications of HMGB1 in cancer need further in-depth studies.

Histone deacetylase as emerging pharmacological therapeutic target for neuropathic pain: From epigenetic to selective drugs.

Neuropathic pain remains a formidable challenge for modern medicine. The first-line pharmacological therapies exhibit limited efficacy and unfavorable side effect profiles, highlighting an unmet need for effective therapeutic medications. The past decades have witnessed an explosion in efforts to translate epigenetic concepts into pain therapy and shed light on epigenetics as a promising avenue for pain research. Recently, the aberrant activity of histone deacetylase (HDAC) has emerged as a key mechanism contributing to the development and maintenance of neuropathic pain. In this review, we highlight the distinctive role of specific HDAC subtypes in a cell-specific manner in pain nociception, and outline the recent experimental evidence supporting the therapeutic potential of HDACi in neuropathic pain. We have summarized studies of HDAC in neuropathic pain in Pubmed. HDACs, widely distributed in the neuronal and non-neuronal cells of the dorsal root ganglion and spinal cord, regulate gene expression by deacetylation of histone or non-histone proteins and involving in increased neuronal excitability and neuroinflammation, thus promoting peripheral and central sensitization. Importantly, pharmacological manipulation of aberrant acetylation using HDAC-targeted inhibitors (HDACi) has shown promising pain-relieving properties in various preclinical models of neuropathic pain. Yet, many of which exhibit low-specificity that may induce off-target toxicities, underscoring the necessity for the development of isoform-selective HDACi in pain management. Abnormally elevated HDACs promote neuronal excitability and neuroinflammation by epigenetically modulating pivotal gene expression in neuronal and immune cells, contributing to peripheral and central sensitization in the progression of neuropathic pain, and HDACi showed significant efficacy and great potential for alleviating neuropathic pain.

Act88F pseudo-acetylation of lysine 50 (K50) negatively regulates muscle function in Drosophila

Non-histone post-translational modifications (PTMs) are an increasingly important area of study that contribute to our understanding for protein function in the control of health and disease. Protein PTMs, such as acetylation, are emerging as key regulators of striated muscle function, yet our understanding of how non-histone protein acetylation affects muscle physiology remains fragmentary. Previous reports from our lab identified lysine (K) 52 of skeletal muscle alpha actin (ACTA1) to be acetylated, yet no reports have shown a role for ACTA1 acetylation in muscle function. Act88F is 93% homologous to ACTA1 and K50 is identical to K52 of ACTA1. Thus, for these studies, we mutated K50 with a glutamine (Q) on the Act88F gene in the indirect flight muscle (IFM) of Drosophila to mimic acetylation. We examined physiological function (i.e. flight and climbing) as well as biophysical changes between acetylated Act88F and the associated myofibrillar proteins involved in contraction and relaxation (myosin, tropomyosin, and troponin). We report that Act88F K50Q pseudo-acetylation resulted in a flightless phenotype and decreased climbing ability. In addition, we report that Act88F K50Q flies had increased IFM damage as examined via fluorescent imaging. Interestingly, Act88F K50Q did not change actin-myosin binding, actin sliding velocity, or Ca2+ sensitivity in actin-motility assays. However, Act88F pseudo-acetylation did decrease actin filament length, but only after interacting with myosin, implying that Act88F acetylation increases actin filament breaking. These data suggest that Act88F acetylation at K50 worsens muscle function by destabilizing filamentous actin, resulting in muscle tearing and damage to the IFM, which results in loss of flight. This work suggests that actin acetylation, at least on lysine 50, in response to environmental stressors or diet could greatly change muscle function and sarcomere integrity. This research was funded by the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research, the National Institute for General Medical Sciences (NIGMS) of the NIH (P20 GM130459), the National Heart, Lung, and Blood Institute of the NIH (R15 HL143496), National Institute of Aging of the NIH (R21 AG077248) and NSF EPSCOR Track II (OIA-1826801) to B.S.F. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

CARM1 hypermethylates the NuRD chromatin remodeling complex to promote cell cycle gene expression and breast cancer development.

Protein arginine methyltransferase CARM1 has been shown to methylate a large number of non-histone proteins, and play important roles in gene transcriptional activation, cell cycle progress, and tumorigenesis. However, the critical substrates through which CARM1 exerts its functions remain to be fully characterized. Here, we reported that CARM1 directly interacts with the GATAD2A/2B subunit in the nucleosome remodeling and deacetylase (NuRD) complex, expanding the activities of NuRD to include protein arginine methylation. CARM1 and NuRD bind and activate a large cohort of genes with implications in cell cycle control to facilitate the G1 to S phase transition. This gene activation process requires CARM1 to hypermethylate GATAD2A/2B at a cluster of arginines, which is critical for the recruitment of the NuRD complex. The clinical significance of this gene activation mechanism is underscored by the high expression of CARM1 and NuRD in breast cancers, and the fact that knockdown CARM1 and NuRD inhibits cancer cell growth in vitro and tumorigenesis in vivo. Targeting CARM1-mediated GATAD2A/2B methylation with CARM1 specific inhibitors potently inhibit breast cancer cell growth in vitro and tumorigenesis in vivo. These findings reveal a gene activation program that requires arginine methylation established by CARM1 on a key chromatin remodeler, and targeting such methylation might represent a promising therapeutic avenue in the clinic.

Protein Arginine Methyltransferases in Pancreatic Ductal Adenocarcinoma: New Molecular Targets for Therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a low 5-year overall survival rate. It is the third-leading cause of cancer-related deaths in the United States. The lack of robust therapeutics, absence of effective biomarkers for early detection, and aggressive nature of the tumor contribute to the high mortality rate of PDAC. Notably, the outcomes of recent immunotherapy and targeted therapy against PDAC remain unsatisfactory, indicating the need for novel therapeutic strategies. One of the newly described molecular features of PDAC is the altered expression of protein arginine methyltransferases (PRMTs). PRMTs are a group of enzymes known to methylate arginine residues in both histone and non-histone proteins, thereby mediating cellular homeostasis in biological systems. Some of the PRMT enzymes are known to be overexpressed in PDAC that promotes tumor progression and chemo-resistance via regulating gene transcription, cellular metabolic processes, RNA metabolism, and epithelial mesenchymal transition (EMT). Small-molecule inhibitors of PRMTs are currently under clinical trials and can potentially become a new generation of anti-cancer drugs. This review aims to provide an overview of the current understanding of PRMTs in PDAC, focusing on their pathological roles and their potential as new therapeutic targets.