epigenetic alterations
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Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 209
Author(s):  
Dusan Ruzic ◽  
Nemanja Djoković ◽  
Tatjana Srdić-Rajić ◽  
Cesar Echeverria ◽  
Katarina Nikolic ◽  
...  

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.


2022 ◽  
Author(s):  
Mi-Jin An ◽  
Ji-Young Kim ◽  
Jinhong Park ◽  
Jinho Kim ◽  
Dae-Hyun Kim ◽  
...  

Abstract Epigenetic alterations explained by the “loss of heterochromatin” model have been proposed as a universal mechanism of aging, but the region-specific changes of heterochromatin during aging are unclear. Here, we examine age-dependent transcriptomic profiling of mouse retinal neurons to identify epigenetic regulators involved in heterochromatin loss. RNA sequencing analysis revealed gradual down-regulation of Kdm3b during retinal aging. Disruption of Kdm3b (Kdm3b+/-) in 12-month-old mouse retina decreased the number of cone photoreceptors and changed the morphology of cone ribbon synapses. Integration of transcriptome profiling with epigenomic analysis demonstrated gain of heterochromatin feature in synapse assembly and vesicle transport genes via the accumulation of H3K9 mono- and di-methylation. However, the loss of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that this KDM3B-centered epigenomic network is crucial for maintaining cone photoreceptor homeostasis via the modulation of gene-set specific heterochromatin features during aging.


2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Wei Song ◽  
Fei Fei ◽  
Fengchang Qiao ◽  
Zuyi Weng ◽  
Yuanxun Yang ◽  
...  

AbstractLong noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.


Author(s):  
Kaori Hayashi

AbstractRecent studies have demonstrated the association of altered epigenomes with lifestyle-related diseases. Epigenetic regulation promotes biological plasticity in response to environmental changes, and such plasticity may cause a ‘memory effect’, a sustained effect of transient treatment or an insult in the course of lifestyle-related diseases. We investigated the significance of epigenetic changes in several genes required for renal integrity, including the nephrin gene in podocytes, and the sustained anti-proteinuric effect, focusing on the transcription factor Krüppel-like factor 4 (KLF4). We further reported the role of the DNA repair factor lysine-acetyl transferase 5 (KAT5), which acts coordinately with KLF4, in podocyte injury caused by a hyperglycemic state through the acceleration of DNA damage and epigenetic alteration. In contrast, KAT5 in proximal tubular cells prevents acute kidney injury via glomerular filtration regulation by an epigenetic mechanism as well as promotion of DNA repair, indicating the cell type-specific action and roles of DNA repair factors. This review summarizes epigenetic alterations in kidney diseases, especially DNA methylation, and their utility as markers and potential therapeutic targets. Focusing on transcription factors or DNA damage repair factors associated with epigenetic changes may be meaningful due to their cell-specific expression or action. We believe that a better understanding of epigenetic alterations in the kidney will lead to the development of a novel strategy for chronic kidney disease (CKD) treatment.


2022 ◽  
Vol 2 ◽  
Author(s):  
Ye Li ◽  
Xitong Zhao ◽  
Meng Sun ◽  
Dandan Pei ◽  
Ang Li

Stem cells derived from dental tissues (DSCs) exhibit multipotent regenerative potential in pioneering tissue engineering regimens. The multipotency of DSCs is critically regulated by an intricate range of factors, of which the epigenetic influence is considered vital. To gain a better understanding of how epigenetic alterations are involved in the DSC fate determination, the present review overviews the current knowledge relating to DSC epigenetic modifications, paying special attention to the landscape of epigenetic modifying agents as well as the related signaling pathways in DSC regulation. In addition, insights into the future opportunities of epigenetic targeted therapies mediated by DSCs are discussed to hold promise for the novel therapeutic interventions in future translational medicine.


2022 ◽  
Author(s):  
Albert Agustinus ◽  
Ramya Raviram ◽  
Bhargavi Dameracharla ◽  
Jens Luebeck ◽  
Stephanie Stransky ◽  
...  

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers [1-4], yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei [5, 6], and subsequent micronuclear envelope rupture [7] profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and non-transformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer.


Author(s):  
Priyadarshni Patel ◽  
Jeganathan Ramesh Babu ◽  
Xu Wang ◽  
Thangiah Geetha

Obesity is caused by a combination of hereditary and environmental factors. Despite extensive study, contemporary through diet, exercise, education, surgery, and pharmacological treatments, no effective long-term solution has been found to this epidemic. Over the last decade, there has been a tremendous advancement in understanding the science of epigenetics, as well as a rise in public interest in learning more about the influence of diet and lifestyle choices on the health of an individual. Without affecting the underlying DNA sequence, epigenetic alterations impact gene expression. Previous animal studies have shown a link between the type of diet and expression or suppression of obesity genes, but there are very few human studies that demonstrate the relationship between dietary intake and obesity gene expression. This review highlights the effects of carbohydrates, lipids, and protein intake from the diet on obesity-related genes.


2022 ◽  
Author(s):  
Aina Bellver-Sanchis ◽  
Pedro Ávila-López ◽  
Júlia Companys-Alemany ◽  
Gemma Navarro ◽  
Laura Marsal-García ◽  
...  

Abstract Epigenetic alterations are a fundamental pathological hallmark of Alzheimer’s disease (AD). Herein, we uncover the unknown G9a modulation pathways involved in AD, showing the upregulation of G9a and H3K9me2 in the brains of AD patients. Likewise, treatment with a G9a inhibitor in SAMP8 mice reversed the high levels of H3K9me2 and rescued the cognitive decline. Interestingly, a transcriptional profile analysis revealed induction of neuronal plasticity and a reduction of oxidative stress and neuroinflammation; the latter being also validated in cell cultures. Furthermore, an exploratory H3K9me2 ChIP-seq analysis demonstrated that during G9a inhibition treatment, the H3K9me2 mark is enriched at the promoter of genes associated with neural functions. Lastly, we showed in Caenorhabditis elegans (C. elegans) AD transgenic strains, similar epigenetic modifications and modulated pathways were altered with increased β-amyloid levels, which were reverted by the set-25 (in C. elegans is similar to the mammalian G9a protein) knockout, including the cognitive impairment. Therefore, our findings confirm that RNAi suppression of set-25 or pharmacological G9a inhibition promotes a positive outcome in AD, being a promising therapeutic strategy.


2022 ◽  
Author(s):  
Jiahui Mou ◽  
Meijun Huang ◽  
Feifei Wang ◽  
Xiaoding Xu ◽  
Hanqi Xie ◽  
...  

Epigenetic alterations are widely linked with carcinogenesis, therefore becoming emerging therapeutic targets in the treatment of cancers, including breast cancer. HMGNs are nucleosome binding proteins, which regulate chromatin structures in a cell type- and disease-specific manner. However, the roles of HMGNs in the tumorigenesis of breast cancer are less known. In this study, we report that HMGNs are highly expressed in 3D-cultured breast cancer cells. HMGN5, a member of HMGNs, controls the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Clinically, HMGN5 is an unfavorable prognostic marker in patients. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape oncogenic chromatin landscape and transcriptional program. Lastly, we provide evidence that interference of HMGN5 by nanoparticle-packaged siRNA is potentially an effective approach in breast cancer treatment. Taken together, our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic-target in STAT3-hyperactive breast cancer.


2022 ◽  
Vol 13 ◽  
Author(s):  
Eugenie Peze-Heidsieck ◽  
Tom Bonnifet ◽  
Rania Znaidi ◽  
Camille Ravel-Godreuil ◽  
Olivia Massiani-Beaudoin ◽  
...  

The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.


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