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Nature Aging Dec 2023Information storage and retrieval is essential for all life. In biology, information is primarily stored in two distinct ways: the genome, comprising nucleic acids, acts... (Review)
Review
Information storage and retrieval is essential for all life. In biology, information is primarily stored in two distinct ways: the genome, comprising nucleic acids, acts as a foundational blueprint and the epigenome, consisting of chemical modifications to DNA and histone proteins, regulates gene expression patterns and endows cells with specific identities and functions. Unlike the stable, digital nature of genetic information, epigenetic information is stored in a digital-analog format, susceptible to alterations induced by diverse environmental signals and cellular damage. The Information Theory of Aging (ITOA) states that the aging process is driven by the progressive loss of youthful epigenetic information, the retrieval of which via epigenetic reprogramming can improve the function of damaged and aged tissues by catalyzing age reversal.
Topics: Epigenesis, Genetic; DNA Methylation; Information Theory; Histones
PubMed: 38102202
DOI: 10.1038/s43587-023-00527-6 -
European Journal of Internal Medicine Aug 2023Epigenetics is a rapidly growing field of biology that studies the changes in gene expression that are not due to alterations in the DNA sequence but rather the chemical... (Review)
Review
Epigenetics is a rapidly growing field of biology that studies the changes in gene expression that are not due to alterations in the DNA sequence but rather the chemical modifications of DNA and its associated proteins. Epigenetic mechanisms can profoundly influence gene expression, cell differentiation, tissue development, and disease susceptibility. Understanding epigenetic changes is essential to elucidate the mechanisms underlying the increasingly recognized role of environmental and lifestyle factors in health and disease and the intergenerational transmission of phenotypes. Recent studies suggest epigenetics may be critical in various diseases, from cardiovascular disease and cancer to neurodevelopmental and neurodegenerative disorders. Epigenetic modifications are potentially reversible and could provide new therapeutic avenues for treating these diseases using epigenetic modulators. Moreover, epigenetics provide insight into disease pathogenesis and biomarkers for disease diagnosis and risk stratification. Nevertheless, epigenetic interventions have the potential for unintended consequences and may potentially lead to increased risks of unexpected outcomes, such as adverse drug reactions, developmental abnormalities, and cancer. Therefore, rigorous studies are essential to minimize the risks associated with epigenetic therapies and to develop safe and effective interventions for improving human health. This article provides a synthetic and historical view of the origin of epigenetics and some of the most relevant achievements.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Neoplasms
PubMed: 37277249
DOI: 10.1016/j.ejim.2023.05.036 -
Molecular Cell Jan 2024Aging, as a complex process involving multiple cellular and molecular pathways, is known to be exacerbated by various stresses. Because responses to these stresses, such... (Review)
Review
Aging, as a complex process involving multiple cellular and molecular pathways, is known to be exacerbated by various stresses. Because responses to these stresses, such as oxidative stress and genotoxic stress, are known to interplay with the epigenome and thereby contribute to the development of age-related diseases, investigations into how such epigenetic mechanisms alter gene expression and maintenance of cellular homeostasis is an active research area. In this review, we highlight recent studies investigating the intricate relationship between stress and aging, including its underlying epigenetic basis; describe different types of stresses that originate from both internal and external stimuli; and discuss potential interventions aimed at alleviating stress and restoring epigenetic patterns to combat aging or age-related diseases. Additionally, we address the challenges currently limiting advancement in this burgeoning field.
Topics: Epigenesis, Genetic; DNA Methylation; Epigenome; Oxidative Stress
PubMed: 37963471
DOI: 10.1016/j.molcel.2023.10.006 -
Nature Chemical Biology Aug 2023
Topics: DNA Methylation; Sequence Analysis, DNA; High-Throughput Nucleotide Sequencing
PubMed: 37322154
DOI: 10.1038/s41589-023-01356-9 -
Hypertension (Dallas, Tex. : 1979) Aug 2023
Topics: DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans
PubMed: 37470774
DOI: 10.1161/HYPERTENSIONAHA.123.21197 -
Epigenetics Dec 2023DNA methylation, one of the best characterized epigenetic marks in the human genome, plays a pivotal role in gene transcription regulation and other biological processes...
DNA methylation, one of the best characterized epigenetic marks in the human genome, plays a pivotal role in gene transcription regulation and other biological processes in humans. On top of that, the DNA methylome undergoes profound changes in cancer and other disorders. However, large-scale and population-based studies are limited by high costs and the need for considerable expertise in data analysis for whole-genome bisulphite-sequencing methodologies. Following the success of the EPIC DNA methylation microarray, the newly developed Infinium HumanMethylationEPIC version 2.0 (900K EPIC v2) is now available. This new array contains more than 900,000 CpG probes covering the human genome and excluding masked probes from the previous version. The 900K EPIC v2 microarray adds more than 200,000 probes covering extra DNA cis-regulatory regions such as enhancers, super-enhancers and CTCF binding regions. Herein, we have technically and biologically validated the new methylation array to show its high reproducibility and consistency among technical replicates and with DNA extracted from FFPE tissue. In addition, we have hybridized primary normal and tumoural tissues and cancer cell lines from different sources and tested the robustness of the 900K EPIC v2 microarray when analysing the different DNA methylation profiles. The validation highlights the improvements offered by the new array and demonstrates the versatility of this updated tool for characterizing the DNA methylome in human health and disease.
Topics: Humans; DNA Methylation; Epigenome; Reproducibility of Results; Microarray Analysis; Cell Line
PubMed: 36871255
DOI: 10.1080/15592294.2023.2185742 -
Nature Chemical Biology Aug 2023
Topics: DNA Methylation; Demethylation
PubMed: 37500897
DOI: 10.1038/s41589-023-01398-z -
Clinical Cancer Research : An Official... Apr 2024We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and...
PURPOSE
We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.
EXPERIMENTAL DESIGN
AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination.
RESULTS
AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone.
CONCLUSIONS
The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217.
Topics: Animals; Humans; Mice; Rats; Antineoplastic Agents, Alkylating; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; DNA; Glioma; O(6)-Methylguanine-DNA Methyltransferase; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 37967136
DOI: 10.1158/1078-0432.CCR-23-2094 -
Organic & Biomolecular Chemistry May 2024Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions.... (Review)
Review
Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions. Friedel-Crafts alkylation and acylation are arguably some of the most well-known and used synthetic methods for the preparation of small molecules but their use in biological and medical fields is relatively less frequent than the other reactions, possibly owing to the notion of their plausible incompatibility with biological systems. This review demonstrates advances in Friedel-Crafts alkylation and acylation reactions in a variety of biomolecular chemistry fields. With the discoveries and applications of numerous biomolecule-catalyzed or -assisted processes, these reactions have garnered considerable interest in biochemistry, enzymology, and biocatalysis. Despite the challenges of reactivity and selectivity of biomolecular reactions, the alkylation and acylation reactions demonstrated their utility for the construction and functionalization of all the four major biomolecules (, nucleosides, carbohydrates/saccharides, lipids/fatty acids, and amino acids/peptides/proteins), and their diverse applications in biological, medical, and material fields are discussed. As the alkylation and acylation reactions are often fundamental educational components of organic chemistry courses, this review is intended for both experts and nonexperts by discussing their basic reaction patterns (with the depiction of each reaction mechanism in the ESI) and relevant real-world impacts in order to enrich chemical research and education. The significant growth of biomolecular Friedel-Crafts reactions described here is a testament to their broad importance and utility, and further development and investigations of the reactions will surely be the focus in the organic biomolecular chemistry fields.
Topics: Alkylation; Acylation; Proteins; Amino Acids; Carbohydrates; Fatty Acids; Lipids; Nucleosides; Peptides
PubMed: 38624091
DOI: 10.1039/d4ob00406j -
Neuro-oncology Jul 2023Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of...
BACKGROUND
Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double-strand break (DSB) repair and a combination of KDM1A inhibitor and temozolomide (TMZ) in vitro and in vivo using patient-derived glioma stem cells (GSCs).
METHODS
Brain bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. The effect of a combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, RT-qPCR, western blot, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo.
RESULTS
TCGA analysis showed KDM1A is highly expressed in TMZ-treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and self-renewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the blood-brain barrier. CUT&Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity and enhanced TMZ-mediated DNA damage. A combination of KDM1A knockdown or inhibition and TMZ treatment significantly enhanced the survival of tumor-bearing mice.
CONCLUSIONS
Our results provide evidence that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA DSB repair pathways.
Topics: Animals; Mice; Temozolomide; Glioblastoma; Lysine; DNA Breaks, Double-Stranded; Tandem Mass Spectrometry; Cell Line, Tumor; Glioma; DNA Repair; DNA; Histone Demethylases; Drug Resistance, Neoplasm; Antineoplastic Agents, Alkylating; Brain Neoplasms; Xenograft Model Antitumor Assays
PubMed: 36652263
DOI: 10.1093/neuonc/noad018