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Frontiers in Bioscience (Scholar... Jun 2024
Topics: Metals, Heavy; Epigenesis, Genetic; Plants; Stress, Physiological
PubMed: 38939977
DOI: 10.31083/j.fbs1602013 -
Aging Cell Jun 2024Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the...
Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigenetic clocks, including those developed by Horvath and Hannum, DNAmPhenoAge, and with a focus on Index, a new principal component-based epigenetic clock that, like DNAmPhenoAge, is trained to predict an individual's "PhenoAge." We identified significant associations between tHcy levels and ROA, suggesting that hyperhomocysteinemic individuals were aging at a faster rate. Moreover, Index revealed a normalization of accelerated epigenetic aging in these individuals following treatment with tHcy-lowering B-vitamins. Our results indicate that elevated tHcy is a risk factor for accelerated epigenetic aging, and this can be ameliorated with B-vitamins. These findings have broad relevance for the sizable proportion of the worldwide population with elevated tHcy.
PubMed: 38937999
DOI: 10.1111/acel.14255 -
Nature Cancer Jun 2024Epigenetic dysregulation is increasingly appreciated as a hallmark of cancer, including disease initiation, maintenance and therapy resistance. As a result, there have... (Review)
Review
Epigenetic dysregulation is increasingly appreciated as a hallmark of cancer, including disease initiation, maintenance and therapy resistance. As a result, there have been advances in the development and evaluation of epigenetic therapies for cancer, revealing substantial promise but also challenges. Three epigenetic inhibitor classes are approved in the USA, and many more are currently undergoing clinical investigation. In this Review, we discuss recent developments for each epigenetic drug class and their implications for therapy, as well as highlight new insights into the role of epigenetics in cancer.
Topics: Humans; Neoplasms; Epigenesis, Genetic; Epigenome; Antineoplastic Agents; DNA Methylation; Histone Deacetylase Inhibitors; Molecular Targeted Therapy; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38937652
DOI: 10.1038/s43018-024-00777-2 -
Communications Chemistry Jun 2024Epigenetic processes influence health and disease through mechanisms which alter gene expression. In contrast to genetic changes which affect DNA sequences, epigenetic...
Epigenetic processes influence health and disease through mechanisms which alter gene expression. In contrast to genetic changes which affect DNA sequences, epigenetic marks include DNA base modifications or post-translational modification (PTM) of proteins. Histone methylation is a prominent and versatile example of an epigenetic marker: gene expression or silencing is dependent on the location and extent of the methylation. Protein methyltransferases exhibit functional redundancy and broad preferences for multiple histone residues, which presents a challenge for the study of their individual activities. We developed an isotopically labelled analogue of co-factor S-adenosyl-L-methionine (CD-BrSAM), with selectivity for the histone lysine methyltransferase DOT1L, permitting tracking of methylation activity by mass spectrometry (MS). This concept could be applied to other methyltransferases, linking PTM discovery to enzymatic mediators.
PubMed: 38937590
DOI: 10.1038/s42004-024-01227-x -
Scientific Reports Jun 2024The Lys-Asp-Glu-Leu receptor (KDELR) family genes play critical roles in a variety of biological processes in different tumors. Our study aimed to provide a...
The Lys-Asp-Glu-Leu receptor (KDELR) family genes play critical roles in a variety of biological processes in different tumors. Our study aimed to provide a comprehensive analysis of the potential roles of KDELRs in lung adenocarcinoma (LUAD). Utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, as well as clinical samples, we conducted a series of analyses and validations using R software tools and various online resources. The results showed that KDELR family genes and proteins were highly expressed and associated with a poor prognosis of LUAD. Promoter hypomethylation and the competing endogenous RNA (ceRNA) network of PCAT6/hsa-miR-326/KDELR1 might be potential causes of aberrant KDELR1 overexpression in LUAD. Three key Transcription factors (TFs) (SPI1, EP300, and MAZ) and a TFs-miRNAs-KDELRs network (involving 11 TFs) might be involved in modulating KDELRs expression abnormalities. Gene Set Enrichment Analysis (GSEA) indicated enrichment of genes highly expressing KDELR1, KDELR2, and KDELR3 in MTORC1_SIGNALING, P53_PATHWAY, and ANGIOGENESIS. Negative correlations between KDELRs expression and CD8 + T cell infiltration, as well as CTLA-4 expression. Our multiple analyses suggested that the KDELRs are important signaling molecules in LUAD. These results provided novel insights for developing prognostic markers and novel therapies of LUAD.
Topics: Humans; Adenocarcinoma of Lung; Lung Neoplasms; Gene Expression Regulation, Neoplastic; Prognosis; Biomarkers, Tumor; Gene Regulatory Networks; DNA Methylation; Gene Expression Profiling; MicroRNAs
PubMed: 38937522
DOI: 10.1038/s41598-024-65425-2 -
GeroScience Jun 2024Diabetes mellitus type 2 (T2D) is associated with accelerated biological aging and the increased risk of onset of other age-related diseases. Epigenetic changes in DNA...
Diabetes mellitus type 2 (T2D) is associated with accelerated biological aging and the increased risk of onset of other age-related diseases. Epigenetic changes in DNA methylation levels have been found to serve as reliable biomarkers for biological aging. This study explores the relationship between various epigenetic biomarkers of aging and diabetes risk using longitudinal data. Data from the Swedish Adoption/Twin Study of Aging (SATSA) was collected from 1984 to 2014 and included 536 individuals with at least one epigenetic measurement. The following epigenetic biomarkers of aging were employed: DNAm PAI-1, DNAmTL, DunedinPACE, PCHorvath1, PCHorvath2, PCHannum, PCPhenoAge, and PCGrimAge. Firstly, longitudinal analysis of biomarker trajectories was done. Secondly, linear correlations between the biomarkers and time to diabetes were studied within individuals developing diabetes. Thirdly, Cox proportional hazards (PH) models were used to assess the associations between these biomarkers and time of diabetes diagnosis, with adjustments for chronological age, sex, education, smoking, blood glucose, and BMI. The longitudinal trajectories of the biomarkers revealed differences between individuals with and without diabetes. Smoothened average curves for DunedinPACE and DNAm PAI-1 were higher for individuals with diabetes around the age 60-70, compared to controls. Likewise, DunedinPACE and DNAm PAI-1 were higher closer to diabetes onset. However, no significant associations were found between the epigenetic biomarkers of aging and risk of diabetes in Cox PH models. Our findings suggest the potential value of developing epigenetic biomarkers specifically tailored to T2D, should we wish to model and explore the potential for predicting the disease.
PubMed: 38937415
DOI: 10.1007/s11357-024-01252-7 -
Journal of Neuro-oncology Jun 2024Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in...
PURPOSE
Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations.
METHODS
We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases.
RESULTS
Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations.
CONCLUSION
DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.
PubMed: 38937309
DOI: 10.1007/s11060-024-04733-z -
Discover Oncology Jun 2024Acute myeloid leukemia, constituting a majority of leukemias, grapples with a 24% 5-year survival rate. Recent strides in research have unveiled fresh targets for drug...
BACKGROUND
Acute myeloid leukemia, constituting a majority of leukemias, grapples with a 24% 5-year survival rate. Recent strides in research have unveiled fresh targets for drug therapies. LIM-only, a pivotal transcription factor within LIM proteins, oversees cell development and is implicated in tumor formation. Among these critical LIM proteins, CSRP1, a Cysteine-rich protein, emerges as a significant player in various diseases. Despite its recognition as a potential prognostic factor and therapeutic target in various cancers, the specific link between CSRP1 and acute myeloid leukemia remains unexplored. Our previous work, identifying CSRP1 in a prognostic model for AML patients, instigates a dedicated exploration into the nuanced role of CSRP1 in acute myeloid leukemia.
METHODS
R tool was conducted to analyze the public data. qPCR was applied to evaluate the expression of CSRP1 mRNA for clinical samples and cell line. Unpaired t test, Wilcoxon Rank Sum test, KM curves, spearman correlation test and Pearson correlation test were included in this study.
RESULTS
CSRP1 displays notable expression variations between normal and tumor samples in acute myeloid leukemia (AML). It stands out as an independent prognostic factor for AML patients, showing correlations with clinical factors like age and cytogenetics risk. Additionally, CSRP1 correlates with immune-related pathways, immune cells, and immune checkpoints in AML. Furthermore, the alteration of CSRP1 mRNA levels is observed upon treatment with a DNMT1 inhibitor for THP1 cells.
CONCLUSION
The CSRP1 has potential as a novel prognostic factor and appears to influence the immune response in acute myeloid leukemia. Additionally, there is an observed association between CSRP1 and DNA methylation in acute myeloid leukemia.
PubMed: 38937285
DOI: 10.1007/s12672-024-01088-9 -
Cell Stress & Chaperones Jun 2024Epigenetic variations result from long-term adaptation to environmental factors. The Bos indicus (zebu) adapted to tropical conditions whereas Bos taurus to temperate...
Epigenetic variations result from long-term adaptation to environmental factors. The Bos indicus (zebu) adapted to tropical conditions whereas Bos taurus to temperate conditions, hence the native zebu cattle and its crossbred (B indicus X B taurus) show differences in responses to heat stress. The present study evaluated genome-wide DNA methylation profiles of these two breeds of cattle that may explain distinct heat stress responses. Physiological responses to heat stress and estimated values of Iberia heat tolerance coefficient (HTC) and Benezra's coefficient of adaptability (BCA) revealed better relative thermo-tolerance of Hariana compared to the Vrindavani cattle. Genome-wide DNA methylation patterns were different for Hariana and Vrindavani cattle. The comparison between breeds indicated presence of 4599 significant differentially methylated CpGs (DMC) with 756 hyper-methylated and 3845 hypo-methylated in Hariana compared to the Vrindavani cattle. Further, we found 79 genes that showed both differential methylation and differential expression that are involved cellular stress response functions. Differential methylations in the microRNA coding sequences also revealed their functions in heat stress responses. Taken together, epigenetic differences represent potential regulation of long-germ adaptation of Hariana (B indicus) cattle to the tropical environment and relative thermotolerance.
PubMed: 38936463
DOI: 10.1016/j.cstres.2024.06.005 -
Molecular Cell Jun 2024The bacterial world offers diverse strains for understanding medical and environmental processes and for engineering synthetic biological chassis. However, genetically...
The bacterial world offers diverse strains for understanding medical and environmental processes and for engineering synthetic biological chassis. However, genetically manipulating these strains has faced a long-standing bottleneck: how to efficiently transform DNA. Here, we report imitating methylation patterns rapidly in TXTL (IMPRINT), a generalized, rapid, and scalable approach based on cell-free transcription-translation (TXTL) to overcome DNA restriction, a prominent barrier to transformation. IMPRINT utilizes TXTL to express DNA methyltransferases from a bacterium's restriction-modification systems. The expressed methyltransferases then methylate DNA in vitro to match the bacterium's DNA methylation pattern, circumventing restriction and enhancing transformation. With IMPRINT, we efficiently multiplex methylation by diverse DNA methyltransferases and enhance plasmid transformation in gram-negative and gram-positive bacteria. We also develop a high-throughput pipeline that identifies the most consequential methyltransferases, and we apply IMPRINT to screen a ribosome-binding site library in a hard-to-transform Bifidobacterium. Overall, IMPRINT can enhance DNA transformation, enabling the use of sophisticated genetic manipulation tools across the bacterial world.
PubMed: 38936361
DOI: 10.1016/j.molcel.2024.06.003