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Molecular Cell Sep 2023Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants...
Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (mA) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the mA and BUD-23/BUD23 as the mG methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.
Topics: Animals; RNA, Ribosomal, 18S; Caenorhabditis elegans; Hormesis; Methyltransferases; Adenosine
PubMed: 37689068
DOI: 10.1016/j.molcel.2023.08.014 -
Journal of Advanced Research Jul 2024The tumor-associated microbiota plays a vital role in cancer development. Accumulating evidence shows that Fusobacterium nucleatum (Fn) participates in the progression...
INTRODUCTION
The tumor-associated microbiota plays a vital role in cancer development. Accumulating evidence shows that Fusobacterium nucleatum (Fn) participates in the progression of multiple tumor types. However, the underlying mechanisms remain unclear.
OBJECTIVES
This study examined the expression of methyltransferase-like protein 3 (METTL3) during Fn infection and elucidated the function and pathway of Fn-induced m6A methylation in esophageal squamous cell carcinoma (ESCC).
METHODS
The abundance of Fn in patient tissues was determined by qPCR. Western blot, qRT-PCR, and immunohistochemistry were performed to measure METTL3 expression in cells and tissues. METTL3 function was evaluated in vitro by colony formation and cell migration assays. MeRIP-qPCR was performed to determine the relationship between METTL3 and c-Myc. In addition, the half-lives of genes that are downstream of METTL3 were determined with RNA stability assays.
RESULTS
Fn was enriched in hepatocellular carcinoma (HCC), breast cancer (BRCA), ESCC, and colorectal cancer (CRC) tumor tissues. METTL3 expression was positively associated with Fn abundance in ESCC tissues. Fn could survive and proliferation as well as increase METTL3 expression in ESCC, HCC, CRC, and BRCA cells. Moreover, METTL3 overexpression promoted ESCC cells proliferation, migration in vivo and in vitro. Mechanistically, Intracellular Fn infection increases METTL3 transcription. METTL3 promoted c-Myc mRNA methylation in the 3'-untranslated Region (3'-UTR) and enhanced its mRNA stability in a YTH N6-Methyladenosine RNA binding protein 1(YTHDF1)-dependent manner, which contributes to Fn induced ESCC proliferation and metastasis.
CONCLUSIONS
This study indicates that intracellular Fn infection promotes ESCC development and metastasis, and eradicating Fn infection may be a promising strategy for treating ESCC.
Topics: Humans; Methyltransferases; Esophageal Squamous Cell Carcinoma; Fusobacterium nucleatum; Esophageal Neoplasms; Cell Line, Tumor; Fusobacterium Infections; Cell Proliferation; Cell Movement; Female; Gene Expression Regulation, Neoplastic; Methylation; Male; Adenosine; Animals; Neoplasm Metastasis; Mice; Proto-Oncogene Proteins c-myc; Middle Aged
PubMed: 37619934
DOI: 10.1016/j.jare.2023.08.014 -
Neuropharmacology Oct 2023The purinergic system includes P1 and P2 receptors, which are activated by ATP and its metabolites. They are expressed in adult neuronal and glial cells and are crucial... (Review)
Review
The purinergic system includes P1 and P2 receptors, which are activated by ATP and its metabolites. They are expressed in adult neuronal and glial cells and are crucial in brain function, including neuromodulation and neuronal signaling. As P1 and P2 receptors are expressed throughout embryogenesis and development, purinergic signaling also has an important role in the development of the peripheral and central nervous system. In this review, we present the expression pattern and activity of purinergic receptors and of their signaling pathways during embryonic and postnatal development of the nervous system. In particular, we review the involvement of the purinergic signaling in all the crucial steps of brain development i.e. in neural stem cell proliferation, neuronal differentiation and migration as well as in astrogliogenesis and oligodendrogenesis. Then, we review data showing a crucial role of the ATP and adenosine signaling pathways in the formation of the peripheral neuromuscular junction and of central GABAergic and glutamatergic synapses. Finally, we examine the consequences of deregulation of the purinergic system during development and discuss the therapeutic potential of targeting it at adult stage in diseases with reactivation of the ATP and adenosine pathway. This article is part of the Special Issue on "Purinergic Signaling: 50 years".
Topics: Neurons; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Brain; Cell Proliferation
PubMed: 37348675
DOI: 10.1016/j.neuropharm.2023.109640 -
Genes Aug 2023Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic... (Review)
Review
Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), now replaced by a consensus group as metabolic dysfunction-associated steatotic liver disease (MASLD). While excess nutrition and obesity are major contributors to fatty liver, the underlying mechanisms remain largely unknown and therapeutic interventions are limited. Reversible chemical modifications in RNA are newly recognized critical regulators controlling post-transcriptional gene expression. Among these modifications, N6-methyladenosine (m6A) is the most abundant and regulates transcript abundance in fatty liver disease. Modulation of m6A by readers, writers, and erasers (RWE) impacts mRNA processing, translation, nuclear export, localization, and degradation. While many studies focus on m6A RWE expression in human liver pathologies, limitations of technology and bioinformatic methods to detect m6A present challenges in understanding the epitranscriptomic mechanisms driving fatty liver disease progression. In this review, we summarize the RWE of m6A and current methods of detecting m6A in specific genes associated with fatty liver disease.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Adenosine; Computational Biology; Nutritional Status
PubMed: 37628704
DOI: 10.3390/genes14081653 -
Respiratory Research Jul 2023Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a...
BACKGROUND
Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the AR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to ARs in regulating the host's response to T/HS.
METHODS
T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, AR) and conditional knockout (intestinal epithelial cell-specific deficient Villin-AR) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury.
RESULTS
T/HS upregulated the expression of CD39, CD73, and the AR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and AR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and AR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and AR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient Villin-AR mice showed increased intestinal injury compared to their wild-type Villin controls.
CONCLUSION
In conclusion, the CD39-CD73-AR axis protects against T/HS-induced multiple organ failure.
Topics: Animals; Mice; Adenosine; Multiple Organ Failure; Adenosine Triphosphate; Signal Transduction; Bronchoalveolar Lavage Fluid
PubMed: 37438813
DOI: 10.1186/s12931-023-02486-3 -
Nature Structural & Molecular Biology Jan 2024Branching is a critical step in RNA splicing that is essential for 5' splice site selection. Recent spliceosome structures have led to competing models for the...
Branching is a critical step in RNA splicing that is essential for 5' splice site selection. Recent spliceosome structures have led to competing models for the recognition of the invariant adenosine at the branch point. However, there are no structures of any splicing complex with the adenosine nucleophile docked in the active site and positioned to attack the 5' splice site. Thus we lack a mechanistic understanding of adenosine selection and splice site recognition during RNA splicing. Here we present a cryo-electron microscopy structure of a group II intron that reveals that active site dynamics are coupled to the formation of a base triple within the branch-site helix that positions the 2'-OH of the adenosine for nucleophilic attack on the 5' scissile phosphate. This structure, complemented with biochemistry and comparative analyses to splicing complexes, supports a base triple model of adenosine recognition for branching within group II introns and the evolutionarily related spliceosome.
Topics: RNA Splice Sites; Cryoelectron Microscopy; RNA Splicing; Spliceosomes; Introns; Adenosine; RNA Precursors; Nucleic Acid Conformation
PubMed: 38057551
DOI: 10.1038/s41594-023-01150-0 -
Journal of Hematology & Oncology May 2024As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and... (Review)
Review
As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between mA and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target mA regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting mA regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of mA regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure-activity relationships of small molecules targeting mA regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting mA.
Topics: Animals; Humans; Adenosine; Antineoplastic Agents; Epigenesis, Genetic; Neoplasms; Small Molecule Libraries
PubMed: 38711100
DOI: 10.1186/s13045-024-01546-5 -
Frontiers in Immunology 2023Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the... (Review)
Review
Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the ectonucleotides CD39 and CD73. During inflammation Ado is produced by leukocytes and tissue cells by different means to initiate the healing phase. Ado downregulates the activation and the effector functions of different leukocyte (sub-) populations and stimulates proliferation of fibroblasts for re-establishment of intact tissues. Therefore, the anti-inflammatory actions of Ado are already intrinsically triggered during each episode of inflammation. These tissue-regenerating and inflammation-tempering purposes of Ado can become counterproductive. In chronic inflammation, it is possible that Ado-driven anti-inflammatory actions sustain the inflammation and prevent the final clearance of the tissues from possible pathogens. These chronic infections are characterized by increased tissue damage, remodeling and accumulating DNA damage, and are thus prone for tumor formation. Developing tumors may further enhance immunosuppressive actions by producing Ado by themselves, or by "hijacking" CD39/CD73 cells that had already developed during chronic inflammation. This review describes different and mostly convergent mechanisms of how Ado-induced immune suppression, initially induced in inflammation, can lead to tumor formation and outgrowth.
Topics: Humans; Adenosine; Neoplasms; Adenosine Triphosphate; Inflammation; Anti-Inflammatory Agents
PubMed: 38022572
DOI: 10.3389/fimmu.2023.1258637 -
Frontiers in Endocrinology 2023The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression... (Review)
Review
The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of mA and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about mA and mAm modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.
Topics: Humans; RNA, Messenger; Diabetes Mellitus, Type 2; Adenosine; RNA; RNA Processing, Post-Transcriptional
PubMed: 37484960
DOI: 10.3389/fendo.2023.1223583 -
Haematologica Jan 2024
Topics: Humans; Adenosine
PubMed: 37470140
DOI: 10.3324/haematol.2023.283469