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1.
Methods Mol Biol ; 2577: 83-92, 2023.
Article in English | MEDLINE | ID: mdl-36173567

ABSTRACT

Cleavage Under Target & Release Using Nuclease (CUT&RUN) enables the detection of DNA regions that are bound by a protein of interest. This method is suitable for low-input materials because of the absence of an immunoprecipitation step. However, it sometimes fails when applying it to fragile cells, such as mouse oocytes. Here we describe our low-input CUT&RUN protocol optimized for mouse oocyte and preimplantation embryo samples in which the primary antibody and protein A-MNase binding steps are completed before the cells are bound to Concanavalin A-coated magnetic beads. This modification prevents crush of oocytes and early embryos and unwanted loss of chromatin during CUT&RUN procedures.

2.
Methods Mol Biol ; 2519: 141-153, 2023.
Article in English | MEDLINE | ID: mdl-36066719

ABSTRACT

Epigenome research has employed various methods to identify the genomic location of proteins of interest, such as transcription factors and histone modifications. CUT&Tag is a recently established method used in epigenome research to determine the genomic location of proteins of interest, such as transcription factors and histone modifications. In CUT&Tag method, cells are bound and hold on concanavalin A (con A)-coated magnetic beads, then a Protein-A Tn5 transposase fusion protein cuts the genome and inserts adapter sequences nearby the target protein. Here we describe the updated CUT&Tag procedure using "home-made" con A-conjugated magnetic beads. This method is free of poor suspendability and severe aggregation, hence providing improved sensitivity.


Subject(s)
Genome , Histone Code , Concanavalin A , Protein Processing, Post-Translational , Transcription Factors/metabolism
3.
Epigenomics ; 14(5): 279-293, 2022 03.
Article in English | MEDLINE | ID: mdl-35184601

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent form of cancer worldwide. Despite advancements made in treatment strategies, the fatality rate of HNSCC is very high. An accumulating body of evidence suggests that epigenetic modification of histones plays an influential role in the development and progression of the disease. In this review we discuss the role of epigenetic modifications in HNSCC and the inter-relationships of human papillomavirus oncoproteins and histone-modifying agents. Further, we explore the possibility of identifying these modifications as biomarkers for their use as drugs in treatment strategies.


Head and neck squamous cell carcinoma (HNSCC) is the most common kind of head and neck cancer. HNSCC can develop therapeutic resistance, making therapy more difficult. Many studies have found that epigenetic events play a key role in HNSCC. Better understanding epigenetic regulation could help discovery of biomarkers that help detect and diagnose HNSCC. This review will present recent studies, showing the importance of epigenetic regulation targeting histone modifications in the development of HNSCC.


Subject(s)
Head and Neck Neoplasms , Histones , Epigenesis, Genetic , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Histone Code , Histones/metabolism , Humans , Squamous Cell Carcinoma of Head and Neck/genetics
4.
J Mol Cell Cardiol ; 162: 53-61, 2022 01.
Article in English | MEDLINE | ID: mdl-34416247

ABSTRACT

Epigenetic modifications, such as histone or DNA modifications are key regulators of gene transcription and changes are often associated with maladaptive processes underlying cardiovascular disease. Epigenetic regulators therefore likely play a crucial role in cardiomyocyte homeostasis and facilitate the cellular adaption to various internal and external stimuli, responding to different intercellular and extracellular cues. Class IIa histone deacetylases are a class of epigenetic regulators that possess a myriad of post-transcriptional modification sites that modulate their activity in response to oxidative stress, altered catecholamine signalling or changes in the cellular metabolism. This review summaries the known reversible, post-translational modifications (PTMs) of class IIa histone deacetylases (HDACs) that ultimately drive transcriptional changes in homeostasis and disease. We also highlight the idea of a crosstalk of various PTMs on class IIa HDACs potentially leading to compensatory or synergistic effects on the class IIa HDAC-regulated cell behavior.


Subject(s)
Cardiovascular Diseases , Histone Deacetylases , Cardiovascular Diseases/metabolism , Epigenomics , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Humans , Myocytes, Cardiac/metabolism , Protein Processing, Post-Translational
5.
WIREs Mech Dis ; : e1588, 2022 Oct 01.
Article in English | MEDLINE | ID: mdl-36181449

ABSTRACT

Male germ cells undergo an extreme but fascinating process of chromatin remodeling that begins in the testis during the last phase of spermatogenesis and continues through epididymal sperm maturation. Most of the histones are replaced by small proteins named protamines, whose high basicity leads to a tight genomic compaction. This process is epigenetically regulated at many levels, not only by posttranslational modifications, but also by readers, writers, and erasers, in a context of a highly coordinated postmeiotic gene expression program. Protamines are key proteins for acquiring this highly specialized chromatin conformation, needed for sperm functionality. Interestingly, and contrary to what could be inferred from its very specific DNA-packaging function across protamine-containing species, human sperm chromatin contains a wide spectrum of protamine proteoforms, including truncated and posttranslationally modified proteoforms. The generation of protamine knock-out models revealed not only chromatin compaction defects, but also collateral sperm alterations contributing to infertile phenotypes, evidencing the importance of sperm chromatin protamination toward the generation of a new individual. The unique features of sperm chromatin have motivated its study, applying from conventional to the most ground-breaking techniques to disentangle its peculiarities and the cellular mechanisms governing its successful conferment, especially relevant from the protein point of view due to the important epigenetic role of sperm nuclear proteins. Gathering and contextualizing the most striking discoveries will provide a global understanding of the importance and complexity of achieving a proper chromatin compaction and exploring its implications on postfertilization events and beyond. This article is categorized under: Reproductive System Diseases > Genetics/Genomics/Epigenetics Reproductive System Diseases > Molecular and Cellular Physiology.

6.
Mol Biol Rep ; 2022 Oct 01.
Article in English | MEDLINE | ID: mdl-36181582

ABSTRACT

BACKGROUND: Saffron (Crocus sativus) is high valued spice crop, but due to its sterile nature, the crop is propagated exclusively through corms. Thus, the genetic base of this crop is very narrow, however, frequency of phenotypic variability is observed; and suggested the potential role of epigenetics in saffron crop growth and development. METHODS AND RESULTS: To facilitate epigenetic studies in saffron, we developed 1525 methylation-specific PCR (MSP) markers using MethPrimer. For this purpose, we used 6767 EST sequences of saffron available on the NCBI database. We also mine CpG islands (2555) and found that 32.7% of EST sequences had CpG islands. Out of 1525 MSP markers developed during the present study, 725 covered the CpG islands and 800 were without CpG islands. PCR amplification was found successful for 82% of MSP markers. A preliminary analysis suggested that 53.7% of genomic sites were methylated and more prominent (60% methylations) in non-CpG island regions, although, more comprehensive studies are required to validate it further. CONCLUSIONS: The epigenetic resource developed during the present study will strengthen the epigenetic studies like epiQTL mapping, epiGWAS to explore the molecular mechanisms and genomic/epigenomic regions associated with phenotype; and further may be utilized for saffron improvement programs through epibreeding.

7.
Biol Psychiatry ; 2022 Jul 16.
Article in English | MEDLINE | ID: mdl-36182531

ABSTRACT

BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood. METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795). RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts. CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

8.
J Affect Disord ; 319: 142-163, 2022 Sep 13.
Article in English | MEDLINE | ID: mdl-36113690

ABSTRACT

BACKGROUND: Prenatal maternal stress is increasingly recognized as a risk factor for offspring mental health challenges. DNA methylation may be a mechanism, but few studies directly tested mediation. These few integrative studies are reviewed along with studies from three research areas: prenatal maternal stress and child mental health, prenatal maternal stress and child DNA methylation, and child mental health and DNA methylation. METHODS: We conducted a narrative review of articles in each research area and the few published integrative studies to evaluate the state of knowledge. RESULTS: Prenatal maternal stress was related to greater offspring internalizing and externalizing symptoms and to greater offspring peripheral DNA methylation of the NR3C1 gene. Youth mental health problems were also related to NR3C1 hypermethylation while epigenome-wide studies identified genes involved in nervous system development. Integrative studies focused on infant outcomes and did not detect significant mediation by DNA methylation though methodological considerations may partially explain these null results. LIMITATIONS: Operationalization of prenatal maternal stress and child mental health varied greatly. The few published integrative studies did not report conclusive evidence of mediation by DNA methylation. CONCLUSIONS: DNA methylation likely mediates the association between prenatal maternal stress and child mental health. This conclusion still needs to be tested in a larger number of integrative studies. Key empirical and statistical considerations for future research are discussed. Understanding the consequences of prenatal maternal stress and its pathways of influence will help prevention and intervention efforts and ultimately promote well-being for both mothers and children.

9.
Biomed Pharmacother ; 153: 113548, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36076614

ABSTRACT

A group of hormones, called estrogens, are pivotal drivers of various physiological processes. Expectedly, estrogen-driven actions are also relevant modulators of pathophysiological changes, including cancer. Different transcriptional and tissue-specific responses are elicited mainly by two estrogen receptor (ER) isoforms, ERα and ERß. Although perturbations of ER subtype-specific expression are correlated with clinical outcomes of cancer, the result strongly depends on co-regulators. Co-regulator acts as a 'bridge' that helps form large protein complexes to modulate transcriptional activity on target gene chromatin. ERs, as transcription factors, may be positively or negatively influenced by the utilisation of different tissue-specific co-regulators. These co-regulators are enzymes that create the epigenetic landscape of histone and DNA modifications, along with proteins that read these modifications and ATP-dependent chromatin remodelers. This review provides an overview and update on ER-driven responses, focusing on the complex interaction between ERs and chromatin modifiers, and discusses how chromatin accessibility and epigenetic modifications contribute to ER recruitment and transactivation.


Subject(s)
Estrogen Receptor beta , Estrogens , Chromatin/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Estrogens/metabolism , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism
11.
Front Oncol ; 12: 962928, 2022.
Article in English | MEDLINE | ID: mdl-36091163

ABSTRACT

A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.

12.
Front Pharmacol ; 13: 984997, 2022.
Article in English | MEDLINE | ID: mdl-36091781

ABSTRACT

Methamphetamine (METH) is an illicit psychostimulant that is widely abused. The molecular mechanism of METH addiction is complicated and still unknown. METH causes the release of the neurotransmitters including dopamine, glutamate, norepinephrine and serotonin, which activate various brain areas in the central nervous system. METH also induces synaptic plasticity and pathological memory enhancement. Epigenetics plays the important roles in regulating METH addiction. This review will briefly summarize the studies on epigenetics involved in METH addiction.

13.
Front Pharmacol ; 13: 958146, 2022.
Article in English | MEDLINE | ID: mdl-36091786

ABSTRACT

DNA methylation is one of the most essential epigenetic mechanisms to regulate gene expression. DNA methyltransferases (DNMTs) play a vital role in DNA methylation in the genome. In mammals, DNMTs act with some elements to regulate the dynamic DNA methylation patterns of embryonic and adult cells. Conversely, the aberrant function of DNMTs is frequently the hallmark in judging cancer, including total hypomethylation and partial hypermethylation of tumor suppressor genes (TSGs), which improve the malignancy of tumors, aggravate the ailment for patients, and significantly exacerbate the difficulty of cancer therapy. Since DNA methylation is reversible, currently, DNMTs are viewed as an important epigenetic target for drug development. However, the impression of DNMTs on cancers is still controversial, and therapeutic methods targeting DNMTs remain under exploration. This review mainly summarizes the relationship between the main DNMTs and cancers as well as regulatory mechanisms and clinical applications of DNMTs in cancer and highlights several forthcoming strategies for targeting DNMTs.

14.
Front Genet ; 13: 885635, 2022.
Article in English | MEDLINE | ID: mdl-36092905

ABSTRACT

The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.

15.
Trends Cancer ; 2022 Sep 09.
Article in English | MEDLINE | ID: mdl-36096997

ABSTRACT

The Hippo pathway is dysregulated in many different cancers, but point mutations in the pathway are rare. Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) fusion proteins have emerged in almost all major cancer types and represent the most common genetic mechanism by which the two transcriptional co-activators are activated. Given that the N termini of TAZ or YAP are fused to the C terminus of another transcriptional regulator, the resultant fusion proteins hyperactivate a TEAD transcription factor-based transcriptome. Recent advances show that the C-terminal fusion partners confer oncogenic properties to TAZ/YAP fusion proteins by recruiting epigenetic modifiers that promote a hybrid TEAD-based transcriptome. Elucidating these cooperating epigenetic complexes represents a strategy to identify new therapeutic approaches for a pathway that has been recalcitrant to medical therapy.

16.
Mol Biotechnol ; 2022 Sep 13.
Article in English | MEDLINE | ID: mdl-36098867

ABSTRACT

Epigenetic regulation by histone modification can activate or repress transcription through changes in chromatin dynamics and regulates development and the response to environmental signals in both animals and plants. Chromatin immunoprecipitation (ChIP) is an indispensable tool to identify histones with specific post-translational modifications. The lack of a ChIP technique for macroalgae has hindered understanding of the role of histone modification in the expression of genes in this organism. In this study, a ChIP method with several modifications, based on existing protocols for plant cells, has been developed for the red macroalga, Neopyropia yezoensis, that consists of a heterogeneous alternation of macroscopic leaf-like gametophytes and microscopic filamentous sporophytes. ChIP method coupled with qPCR enables the identification of a histone mark in generation-specific genes from N. yezoensis. The results indicate that acetylation of histone H3 at lysine 9 in the 5' flanking and coding regions from generation-specific genes was maintained at relatively high levels, even in generation-repressed gene expression. The use of this ChIP method will contribute significantly to identify the epigenetic regulatory mechanisms through histone modifications that control a variety of biological processes in red macroalgae.

17.
Med Law Rev ; 2022 Sep 13.
Article in English | MEDLINE | ID: mdl-36099175

ABSTRACT

Global social movements for justice have called for better legal responses to the harms of inequality. These inequalities have traditionally been dealt with in the political sphere and legal measures to address them have taken little account of emerging knowledge about the biological impact of unequal treatment. We use the concept 'bioinequalities' to foreground the relationship increasingly articulated in studies that show that social stress and trauma associated with unequal treatment have a significant epigenetic and intergenerational impact on the body. This article proposes a way to address the health harms that result from inequality by drawing on the existing concept of the 'hostile environment' in sexual harassment jurisprudence in Australia. Our 'bioinequality' approach focuses on the way that inequality operates in and as a hostile and harmful environment for the embodied and embedded beings that live in it. We examine the possibilities of using the concept of a hostile environment to more effectively address discriminatory harms alongside a positive duty to create non-hostile environments. In so doing we offer a broader, bioscientifically informed approach that can inform equality laws in other jurisdictions.

18.
Front Oncol ; 12: 979569, 2022.
Article in English | MEDLINE | ID: mdl-36059621

ABSTRACT

Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called 'epimutations' have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.

19.
Front Pharmacol ; 13: 955218, 2022.
Article in English | MEDLINE | ID: mdl-36059955

ABSTRACT

Epigenetics has emerged as a prime focus area in the field of cancer research. Lysine-specific demethylase 1A (LSD1), the first discovered histone demethylase, is mainly responsible for catalysing demethylation of histone 3 lysine 4 (H3K4) and H3K9 to activate or inhibit gene transcription. LSD1 is abnormally expressed in various cancers and participates in cancer proliferation, apoptosis, metastasis, invasion, drug resistance and other processes by interacting with regulatory factors. Therefore, it may serve as a potential therapeutic target for cancer. This review summarises the major oncogenic mechanisms mediated by LSD1 and provides a reference for developing novel and efficient anticancer strategies targeting LSD1.

20.
Front Cell Dev Biol ; 10: 909557, 2022.
Article in English | MEDLINE | ID: mdl-36060800

ABSTRACT

The world's population with obesity is reaching pandemic levels. If current trends continue, it is predicted that there will be 1.5 billion people with obesity by 2030. This projection is alarming due to the association of obesity with numerous diseases including cancer, with recent studies demonstrating a positive association with acute myeloid leukemia (AML) and B cell acute lymphoblastic leukemia (B-ALL). Interestingly, several epidemiological studies suggest the converse relationship may exist in patients with T cell acute lymphoblastic leukemia (T-ALL). To determine the relationship between obesity and T-ALL development, we employed the diet-induced obesity (DIO) murine model and cultured human T-ALL cells in adipocyte-conditioned media (ACM), bone marrow stromal cell-conditioned media, stromal conditioned media (SCM), and unconditioned media to determine the functional impact of increased adiposity on leukemia progression. Whereas only 20% of lean mice transplanted with T-ALL cells survived longer than 3 months post-inoculation, 50%-80% of obese mice with leukemia survived over this same period. Furthermore, culturing human T-ALL cells in ACM resulted in increased histone H3 acetylation (K9/K14/K18/K23/K27) and methylation (K4me3 and K27me3) posttranslational modifications (PTMs), which preceded accelerated cell cycle progression, DNA damage, and cell death. Adipocyte-mediated epigenetic changes in human T-ALL cells were recapitulated with the H3K27 demethylase inhibitor GSK-J4 and the pan-HDAC inhibitor vorinostat. These drugs were also highly cytotoxic to human T-ALL cells at low micromolar concentrations. In summary, our data support epidemiological studies demonstrating that adiposity suppresses T-ALL pathogenesis. We present data demonstrating that T-ALL cell death in adipose-rich microenvironments is induced by epigenetic modifications, which are not tolerated by leukemia cells. Similarly, GSK-J4 and vorinostat treatment induced epigenomic instability and cytotoxicity profiles that phenocopied the responses of human T-ALL cells to ACM, which provides additional support for the use of epigenetic modifying drugs as a treatment option for T-ALL.

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