Hallmarks of Cancer: New Dimensions

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(1), P. 31 - 46

Published: Jan. 1, 2022

The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity phenotypes and genotypes into provisional set underlying principles. As knowledge mechanisms has progressed, other facets disease have emerged as potential refinements. Herein, prospect raised that phenotypic plasticity disrupted differentiation discrete hallmark capability, nonmutational epigenetic reprogramming polymorphic microbiomes both constitute distinctive enabling characteristics facilitate acquisition capabilities. Additionally, senescent cells, varying origins, may be added to roster functionally important cell types in tumor microenvironment. SIGNIFICANCE: Cancer daunting breadth scope its diversity, spanning genetics, tissue biology, pathology, response therapy. Ever more powerful experimental computational tools technologies are providing an avalanche "big data" about myriad manifestations diseases encompasses. integrative concept embodied helping distill this increasingly logical science, new dimensions presented perspective add value endeavor, fully understand development malignant progression, apply medicine.

Language: Английский

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Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification

Endocrine Reviews, Journal Year: 2022, Volume and Issue: 43(6), P. 927 - 965

Published: Jan. 13, 2022

Polycystic ovary syndrome (PCOS) is among the most common disorders in women of reproductive age, affecting up to 15% worldwide, depending on diagnostic criteria. PCOS characterized by a constellation interrelated abnormalities, including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It frequently associated with insulin resistance obesity. These metabolic derangements cause major morbidities across lifespan, anovulatory infertility type 2 diabetes (T2D). Despite decades investigative effort, etiology remains unknown. Familial clustering cases has indicated genetic contribution PCOS. There are rare Mendelian forms extreme phenotypes, but typically follows non-Mendelian pattern inheritance consistent complex architecture, analogous T2D obesity, that reflects interaction susceptibility genes environmental factors. Genomic studies have provided important insights into disease pathways current criteria do not capture underlying differences biology different We provide state-of-the-science review analyses PCOS, an overview genomic methodologies aimed at general audience non-geneticists clinicians. Applications will be discussed, strengths limitations each study. The contributions factors, developmental origins, reviewed. Insights pathogenesis architecture summarized. Future directions for outlined.

Language: Английский

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Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(3), P. 513 - 530.e8

Published: Feb. 6, 2021

Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of age. PCOS has a strong heritable component, but its pathogenesis been unclear. Here, we performed RNA sequencing genome-wide DNA methylation profiling ovarian tissue from control third-generation PCOS-like mice. We found that hypomethylation regulates key genes associated with several differentially methylated are also altered in blood samples compared healthy controls. Based on this insight, treated mouse model methyl group donor S-adenosylmethionine it corrected their transcriptomic, neuroendocrine, defects. These findings show transmission traits to future generations occurs via an landscape propose methylome markers as possible diagnostic landmark for condition, while identifying potential candidates epigenetic-based therapy.

Language: Английский

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Insights into epigenetic patterns in mammalian early embryos

Protein & Cell, Journal Year: 2020, Volume and Issue: 12(1), P. 7 - 28

Published: July 15, 2020

Mammalian fertilization begins with the fusion of two specialized gametes, followed by major epigenetic remodeling leading to formation a totipotent embryo. During development pre-implantation embryo, precise reprogramming progress is prerequisite for avoiding developmental defects or embryonic lethality, but underlying molecular mechanisms remain elusive. For past few years, unprecedented breakthroughs have been made in mapping regulatory network dynamic epigenomes during mammalian early embryo development, taking advantage multiple advances and innovations low-input genome-wide chromatin analysis technologies. The aim this review highlight most recent understanding embryogenesis mammals, including DNA methylation, histone modifications, accessibility 3D organization.

Language: Английский

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The interplay between DNA and histone methylation: molecular mechanisms and disease implications

EMBO Reports, Journal Year: 2021, Volume and Issue: 22(5)

Published: April 12, 2021

Language: Английский

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Losing DNA methylation at repetitive elements and breaking bad

Epigenetics & Chromatin, Journal Year: 2021, Volume and Issue: 14(1)

Published: June 3, 2021

Abstract Background DNA methylation is an epigenetic chromatin mark that allows heterochromatin formation and gene silencing. It has a fundamental role in preserving genome stability (including chromosome stability) by controlling both expression structure. Therefore, the onset of incorrect pattern potentially dangerous for cells. This particularly important with respect to repetitive elements, which constitute third human genome. Main body Repetitive sequences are involved several cell processes, however, due their intrinsic nature, they can be source instability. Thus, most elements usually methylated maintain heterochromatic, repressed state. Notably, there increasing evidence showing (satellites, long interspersed nuclear (LINEs), Alus) frequently hypomethylated various pathologies, from cancer psychiatric disorders. sequences’ hypomethylation correlates relaxation unscheduled transcription. If these alterations directly diseases aetiology how, still under investigation. Conclusions Hypomethylation different families recurrent many diseases, suggesting status preservation health. provides promising point view towards research therapeutic strategies focused on specifically tuning repeats.

Language: Английский

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An Epigenetic Role of Mitochondria in Cancer

Cells, Journal Year: 2022, Volume and Issue: 11(16), P. 2518 - 2518

Published: Aug. 13, 2022

Mitochondria are not only the main energy supplier but also cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which substrates for DNA methylation histone post-translation modifications, essential gene transcriptional regulation fate determination. Tumorigenesis is attributed to many factors, including mutations tumor microenvironment. initiation, evolution, metastasis, recurrence. Targeting mitochondrial metabolism promising therapeutic strategies treatment. In this review, we summarize of mitochondria required modification discuss current strategy cancer therapies via targeting epigenetic modifiers related enzymes This review an important contribution understanding metabolic-epigenetic-tumorigenesis concept.

Language: Английский

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Oxidative-Stress-Mediated Epigenetic Dysregulation in Spermatogenesis: Implications for Male Infertility and Offspring Health

Genes, Journal Year: 2025, Volume and Issue: 16(1), P. 93 - 93

Published: Jan. 17, 2025

Male reproductive health is governed by an intricate interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms—encompassing DNA methylation, histone modifications, non-coding RNA activity—are crucial both for spermatogenesis sperm maturation. However, oxidative stress, driven excessive reactive oxygen species, disrupts these processes, leading to impaired function male infertility. This disruption extends epigenetic resulting in abnormal gene expression chromatin remodeling that compromise genomic integrity fertilization potential. Importantly, oxidative-stress-induced alterations can be inherited, affecting the fertility offspring future generations. review investigates how stress influences regulation reproduction modifying RNAs, ultimately compromising spermatogenesis. Additionally, it discusses transgenerational implications disruptions their potential role hereditary infertility disease predisposition. Understanding mechanisms vital developing therapeutic strategies mitigate damage restore homeostasis germline. By integrating insights from molecular, clinical, research, this work emphasizes need targeted interventions enhance prevent adverse outcomes progeny. Furthermore, elucidating dose–response relationships between changes remains a critical research priority, informing personalized diagnostics interventions. In context, studies should adopt standardized markers damage, robust clinical trials, multi-omic approaches capture complexity Such rigorous investigations will reduce risk disorders optimize outcomes.

Language: Английский

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How do lifestyle and environmental factors influence the sperm epigenome? Effects on sperm fertilising ability, embryo development, and offspring health

Clinical Epigenetics, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 16, 2025

Recent studies support the influence of paternal lifestyle and diet before conception on health offspring via epigenetic inheritance through sperm DNA methylation, histone modification, small non-coding RNA (sncRNA) expression regulation. Smoking may induce hypermethylation in genes related to anti-oxidation insulin resistance. Paternal obesity are associated with greater risks metabolic dysfunction alterations sperm. Metabolic changes, such as high blood glucose levels increased body weight, commonly observed fathers subjected chronic stress, addition an enhanced risk depressive-like behaviour sensitivity stress both F0 F1 generations. methylation is correlated quality ability fertilise oocytes, possibly a differentially regulated MAKP81IP3 signalling pathway. exposure toxic endocrine-disrupting chemicals (EDCs) also linked transgenerational transmission predisposition disease, infertility, testicular disorders, obesity, polycystic ovarian syndrome (PCOS) females changes during gametogenesis. As success assisted reproductive technology (ART) affected by diet, BMI, alcohol consumption, its outcomes could be improved modifying factors that dependent male choices environmental factors. This review discusses importance signatures sperm—including retention, sncRNA—for functionality, early embryo development, health. We discuss mechanisms which (obesity, smoking, EDCs, stress) impact epigenome.

Language: Английский

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Staying true to yourself: mechanisms of DNA methylation maintenance in mammals

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 49(6), P. 3020 - 3032

Published: Nov. 11, 2020

Abstract DNA methylation is essential to development and cellular physiology in mammals. Faulty frequently observed human diseases like cancer neurological disorders. Molecularly, this epigenetic mark linked other chromatin modifications it regulates key genomic processes, including transcription splicing. Each round of replication generates two hemi-methylated copies the genome. These must be converted back symmetrically methylated before next S-phase, or will fade away; therefore maintenance essential. Mechanistically, modification takes place during after replication, occurs within very dynamic context re-assembly. Here, we review recent discoveries unresolved questions regarding mechanisms, dynamics fidelity We also discuss how could regulated normal misregulated disease.

Language: Английский

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