The Functional Map of Ultraconserved Regions in Humans, Mice and Rats DOI Creative Commons
Bruno Thiago de Lima Nichio,

Liliane Santana Oliveira,

Ana Carolina Rodrigues

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 28, 2024

Abstract BACKGROUND: Ultraconserved regions (UCRs) encompass 481 DNA segments exceeding 200 base pairs (bp), displaying 100% sequence identity across humans, mice, and rats, indicating profound conservation taxa pivotal functional roles in human health disease. Despite two decades since their discovery, many UCRs remain to be explored owing incomplete annotation, particularly of newly identified long non-coding RNAs (lncRNAs), limited data aggregation large-scale databases. This study offers a comprehensive map UCRs, investigating genomic transcriptomic implications: (i) enriching UCR annotation data, including ancestral genomes; (ii) exploring lncRNAs containing T-UCRs pan-cancers; (iii) elucidating involvement regulatory elements; (iv) analyzing population single-nucleotide variations linked motifs, expression patterns, diseases. RESULTS: Our results indicate that, although high number protein-coding transcripts with (1,945 from 2,303), 1,775 contained outside CDS regions. Focusing on transcripts, 355 are mapped 85 lncRNA genes, 35 them differentially expressed at least one TCGA cancer type, seven strongly associated survival time, 23 according single-cell analysis. Additionally, we elements 373 (77.5%), found 353 SNP-UCRs (with 1% frequency) potential effects, such as motif changes, eQTL potential, associations disease/traits. Finally, 4 novel that had not been previously described. CONCLUSION: report compiles organizes all the above information, providing new insights into mechanisms diagnostic applications.

Language: Английский

Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

Citations

30
Tumor energy metabolism: implications for therapeutic targets DOI Creative Commons

Youwu Hu,

Wanqing Liu,

WanDi Fang

et al.

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: Nov. 29, 2024

Abstract Tumor energy metabolism plays a crucial role in the occurrence, progression, and drug resistance of tumors. The study tumor has gradually become an emerging field treatment. Recent studies have shown that epigenetic regulation is closely linked to metabolism, influencing metabolic remodeling biological traits cells. This review focuses on primary pathways explores therapeutic strategies target these pathways. It covers key areas such as glycolysis, Warburg effect, mitochondrial function, oxidative phosphorylation, adaptability Additionally, this article examines regulator SWI/SNF complex specifically its interactions with glucose, lipids, amino acids. Summarizing aimed at pathways, including inhibitors mitochondrial-targeted drugs, exploitation vulnerabilities, recent developments related complexes potential targets. clinical significance, challenges, future directions research are discussed, overcome resistance, combination therapy, application new technologies.

Language: Английский

Citations

8
Genomic Characterization of Chordoma: Insights from the AACR Project GENIE Database DOI Open Access

Beau Hsia,

Gabriel Bitar,

Saif Alshaka

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(3), P. 536 - 536

Published: Feb. 5, 2025

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to poor understanding of its genomic landscape. This study aims characterize the genetic alterations in chordoma using large national patient-level repository, AACR Project GENIE, identify potential targets and improve disease modeling. Methods: A retrospective analysis samples was conducted GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, mutational burden, chromosomal copy number variations, significance set at p < 0.05. Results: Frequent mutations observed genes associated SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations also common among TERT promoter regions, cell cycle regulation (CDKN2A). Significant co-occurrences identified BRCA2, KMT2D mutations. CDKN2A/B deletions enriched metastatic tumors, pediatric cases demonstrated distinct mutation profiles compared adults. Conclusions: provides profile chordoma, identifying key targets. These findings highlight roles pathways biology, offering insights future precision medicine approaches interventions.

Language: Английский

Citations

0
SWI/SNF complex interacts with CAR to regulate drug-metabolizing enzymes and transporters in the liver DOI Creative Commons

Kiamu Kurosawa,

Masataka Nakano,

Itsuki Yokoseki

et al.

Drug Metabolism and Disposition, Journal Year: 2025, Volume and Issue: unknown, P. 100057 - 100057

Published: March 1, 2025

Constitutive androstane receptor (CAR) is a nuclear that plays an important role in regulating drug metabolism and bile acid homeostasis the liver. Recently, it was revealed switch/sucrose non-fermentable (SWI/SNF) complex, chromatin remodeler, regulates transactivation by receptors, such as pregnane X vitamin D receptor. However, studies on involvement of SWI/SNF complex CAR-mediated are limited. Here, we demonstrated induction cytochrome P450 CYP2B6 expression CAR activators, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime phenobarbital, enhanced inhibition AT-rich interactive domain-containing protein (ARID) 1A, canonical brahma-related gene 1-associated factor (cBAF) component, one complexes, attenuated bromodomain-containing (BRD) 9, noncanonical BAF (ncBAF) primary hepatocytes from humanized mice. Coimmunoprecipitation assays ARID1A BRD9 interacted with CAR. Chromatin immunoprecipitation assay O-(3,4-dichlorobenzyl)oxime-induced binding to 5'-flanking region increased reduced inhibition. These results suggest cBAF negatively attenuating its response element, whereas ncBAF positively facilitating binding. Furthermore, phenobarbital-induced increases UDP-glucuronosyltransferase 1A1 multidrug resistance-associated 2 mRNA level activity. Collectively, our findings indicate play essential roles xenobiotic inhibitors may offer therapeutic benefits for hyperbilirubinemia cholestasis inducing expression. SIGNIFICANCE STATEMENT: This study factor, members family, regulate constitutive transactivation, respectively, through changes structure around element regions target genes. The 1A be beneficial treatment enhancing transactivation.

Language: Английский

Citations

0
Epigenetics and Chromatin Remodeling DOI
H. Karimi Kinyamu, Dimitris Theofilatos, Lantz C. Mackey

et al.

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Impact of mSWI/SNF epigenetic complexes on ionizing radiotherapy resistance in malignant diseases: A comprehensive view in oncology DOI Creative Commons
Octavio A. Trejo-Villegas, Enrique Pérez‐Cárdenas,

Federico Maldonado Magos

et al.

Life Sciences, Journal Year: 2025, Volume and Issue: 374, P. 123690 - 123690

Published: May 8, 2025

The mSWI/SNF chromatin remodeling complexes are critical regulators of genomic stability, particularly in their role orchestrating DNA repair and modulating cellular responses to ionizing radiation therapy. Their involvement has positioned these molecular as key factors determining radiosensitivity human malignant diseases. present review delves into the biomedical contributions specific subunits, including ARID1A, SMARCB1, SMARCA4, PBRM1, BRD9, highlighting pivotal roles influencing tumor radiotherapy. Evidence suggests that loss function often due mutations, disrupts pathways, thereby compromising integrity enhancing susceptibility radiation-induced damage. Emerging preclinical studies have underscored potential exploiting vulnerabilities through pharmacological targeting complexes. Inhibition can impair damage mechanisms, creating a synthetic lethality effect by using combined epigenetic therapy with protocols. This dual approach not only amplifies therapeutic efficacy radiotherapy but also broadens spectrum strategies for oncological However, further investigation mechanisms underlying interactions is essential optimizing therapies paving way clinical applications aimed at outcomes cancer patients.

Language: Английский

Citations

0
Death-ision: the link between cellular resilience and cancer resistance to treatments DOI Creative Commons
Gustavo Baldassarre, Ivana L. de la Serna, François M. Vallette

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: May 15, 2025

Language: Английский

Citations

0
SMARCA4: Promises and challenges in the treatment of Cancers DOI
Wei Ye, An Ding,

Wen‐Bin Ou

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217811 - 217811

Published: May 1, 2025

Language: Английский

Citations

0
Retrospective Insights into the Clinicopathological Features and Treatment Outcomes of Thoracic SMARCA4-Deficient Tumors DOI Creative Commons
Lijin Chen,

Chiu‐Ping Su,

Jiadi Yao

et al.

Technology in Cancer Research & Treatment, Journal Year: 2025, Volume and Issue: 24

Published: May 1, 2025

Introduction Thoracic SMARCA4-deficient tumors, which are rare and aggressive malignancies found in the lung or thoracic cavity, present a challenge treatment standardization. This arises from their resistance to chemotherapy absence of targeted therapy options. Methods tumors were identified retrospectively using pathology databases. The clinicopathological characteristics these outlined, clinical outcomes advanced patients treated with immune checkpoint inhibitors (ICIs) combination alone reviewed. Results Thirty-nine had median age 62 years. cohort consisted 92.3% males, 89.7% history smoking. Within this group, 94.9% stage III/IV disease at diagnosis. non-small cell cancer (SMARCA4-DNSCLC) undifferentiated (SMARCA4-DUT) display distinct histological immunohistochemical features. Thirty-five underwent systemic therapy, achieving an ORR 51.4%, DCR 82.9%, OS 20.9 months. Patients categorized into (28.6%) ICIs plus (71.4%) groups. group exhibited 64.0% 96.0%, while 20.0% 50.0%, respectively ( P < .0001 for DCR). groups months 6.5 months, PFS 9.6 3.5 respectively, all statistically significant .05). Multivariate COX regression analysis indicated that was independent prognostic factor OS. Conclusion exhibit lack SMARCA4 expression, displaying high malignancy aggressiveness exhibiting poor response standard chemotherapy. could potentially serve as effective approach tumors.

Language: Английский

Citations

0
Muscle‐specific pyruvate kinase isoforms, PKM1 and PKM2, regulate mammalian SWI/SNF proteins and histone 3 phosphorylation during myoblast differentiation DOI Creative Commons
Monserrat Olea‐Flores, Tapan Sharma, Odette Verdejo‐Torres

et al.

The FASEB Journal, Journal Year: 2024, Volume and Issue: 38(11)

Published: June 4, 2024

Abstract Pyruvate kinase is a glycolytic enzyme that converts phosphoenolpyruvate and ADP into pyruvate ATP. There are two genes encode in vertebrates; Pkm Pkl muscle‐ liver/erythrocyte‐specific forms, respectively. Each gene encodes isoenzymes due to alternative splicing. Both muscle‐specific enzymes, PKM1 PKM2, function glycolysis, but PKM2 also has been implicated regulation its ability phosphorylate histone 3 threonine 11 (H3T11) cancer cells. Here, we examined the roles of during myoblast differentiation. RNA‐seq analysis revealed promotes expression Dpf2/Baf45d Baf250a/Arid1A . DPF2 BAF250a subunits identify specific sub‐family mammalian SWI/SNF (mSWI/SNF) chromatin remodeling enzymes required for activation myogenic mediated incorporation regulatory sequences controlling expression. did not affect was nuclear localization DPF2. Additionally, only phosphorylated H3T11 promoters H3T6 H3T45 at via AKT protein C isoforms those amino acids. Our results multiple unique novel

Language: Английский

Citations

2