RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(21), С. 11870 - 11870

Опубликована: Ноя. 1, 2021

The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on dynamic nature spatiotemporal patterning gene expression. These features expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, non-coding RNA activity, amongst others. In concert, another regulatory layer by which bases sugar residues chemically modified enhances neuronal transcriptome complexity. Similar modifications other systems collectively constitute epitranscriptome that integrates impacts physiological processes. is reshaped constantly to regulate vital development, differentiation stress responses. Perturbations can lead pathogenic conditions, including cancer, cardiovascular abnormalities neurological diseases. Recent advances next-generation sequencing technologies have enabled us identify locate bases/sugars different species. modulate stability, transport and, most importantly, translation RNA. this review, we discuss formation functions some frequently observed modifications—including methylations adenine cytosine bases, isomerization uridine pseudouridine—at layers metabolism, together with their contributions abnormal conditions neurodevelopmental disorders.

Язык: Английский

---

HybridRNAbind: prediction of RNA interacting residues across structure-annotated and disorder-annotated proteins

Nucleic Acids Research, Год журнала: 2023, Номер 51(5), С. e25 - e25

Опубликована: Янв. 11, 2023

Abstract The sequence-based predictors of RNA-binding residues (RBRs) are trained on either structure-annotated or disorder-annotated binding regions. A recent study protein-binding shows that they plagued by high levels cross-predictions (protein predicted as nucleic acid binding) and structure-trained perform poorly for the regions vice versa. Consequently, we analyze a representative set structure disorder RBRs to comprehensively assess quality their predictions. Our empirical analysis relies new low-similarity benchmark dataset reveals well proteins while disorder-trained provide accurate results proteins. However, these methods work only modestly opposite types annotations, motivating need solutions. Using an approach, design HybridRNAbind meta-model generates predictions low amounts when tested data combines RBRs. We release this convenient webserver which is available at https://www.csuligroup.com/hybridRNAbind/.

Язык: Английский

---

Translational control of Ybx1 expression regulates cardiac function in response to pressure overload in vivo

Basic Research in Cardiology, Год журнала: 2023, Номер 118(1)

Опубликована: Июнь 28, 2023

Abstract RNA–protein interactions are central to cardiac function, but how activity of individual RNA-binding protein is regulated through signaling cascades in cardiomyocytes during heart failure development largely unknown. The mechanistic target rapamycin kinase a hub that controls mRNA translation cardiomyocytes; however, direct link between mTOR and proteins the has not been established. Integrative transcriptome translatome analysis revealed dependent translational upregulation RNA binding Ybx1 early pathological remodeling independent levels. necessary for cardiomyocyte growth by regulating synthesis. To identify molecular mechanisms regulates cellular synthesis, we identified mRNAs bound Ybx1. We discovered eucaryotic elongation factor 2 (Eef2) Ybx1, its upregulated hypertrophy on expression. Eef2 itself sufficient drive increasing global translation. Finally, depletion vivo preserved function hypertrophy. Thus, activation mTORC1 links altered gene expression regulation which turn promotes increased Eef2.

Язык: Английский

---

Promoter regions of sxtA and sxtG reveal relationship between saxitoxin biosynthesis and photosynthesis in toxic Alexandrium catenella

Journal of Applied Phycology, Год журнала: 2024, Номер 36(3), С. 1181 - 1195

Опубликована: Янв. 8, 2024

Язык: Английский

---

RNA BINDING PROTEINS (RBPs) ON GENETIC STABILITY AND DISEASES

Global Medical Genetics, Год журнала: 2025, Номер 12(1), С. 100032 - 100032

Опубликована: Янв. 21, 2025

RNA-binding proteins (RBPs) are integral components of cellular machinery, playing crucial roles in the regulation gene expression and maintaining genetic stability. Their interactions with RNA molecules govern critical processes such as mRNA splicing, stability, localization, translation, which essential for proper function. These interact other to form ribonucleoprotein complexes (RNPs), hence controlling fate target RNAs. The interaction occurs via recognition motif, zinc finger domain, KH domain double stranded binding motif (all known domains (RBDs). found within coding sequences (intron exon domains), 5' untranslated regions (5'UTR) 3' (3'UTR). Dysregulation RBPs can lead genomic instability, contributing various pathologies, including cancer neurodegenerative diseases, metabolic disorders. This study comprehensively explores multifaceted highlighting their involvement integrity through modulation processing implications signalling pathways. Furthermore, it discusses how aberrant RBP function precipitate instability disease progression, emphasizing therapeutic potential targeting restoring homeostasis. Through an analysis current literature, this aims delineate role ensuring stability promise targets innovative strategies.

Язык: Английский

---

PROTAC technology for prostate cancer treatment

Acta Materia Medica, Год журнала: 2025, Номер 4(1)

Опубликована: Янв. 1, 2025

Prostate cancer (PrCa) is the most prevalent urogenital affecting men. PrCa marked by uncontrolled cellular growth that leads to abnormal enlargement of prostate gland. The metastatic spread primary cause mortality, causing cell dissemination distant sites, such as bones, pelvis, and various visceral organs. Key contributors progression include genetic mutations, elevated androgen receptor expression, gene amplification, rise splice variants. Although deprivation therapy remains mainstay for early-stage treatment, efficacy temporary because many cases advance castration-resistant (CRPC), presenting a significant therapeutic hurdle. This review explores key biomarkers latest strategies CRPC with particular focus on innovative proteolysis-targeting chimera (PROTAC) technology. approach offers novel means degrading target proteins we discuss how PROTAC holds potential effective combat resistance mechanisms in CRPC.

Язык: Английский

---

Targeting CHEK2-YBX1&YBX3 regulatory hub to potentiate immune checkpoint blockade response in gliomas

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Although GBM's immunosuppressive environment is well known, the tumor's resistance to CD8+ T cell killing not fully understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as key driver of in mouse glioma through an vivo CRISPR screen and demonstrated that Chk2 inhibition, combined with PD-1/PD-L1 blockade, significantly enhanced cell-mediated tumor improved survival preclinical model. Here, we aimed elucidate function Chek2. Immunoprecipitation (IP) followed by mass spectrometry (MS) phosphoproteomics association between Chek2 DNA/RNA-binding proteins YBX1 YBX3 are implicated transcriptional repression pro-inflammatory genes. Single-gene knock-out overexpression studies CHEK2, YBX1, multiple lines revealed these positively regulate each other's expression. RNA sequencing coupled chromatin immunoprecipitation-sequencing (ChIP-seq) analysis common inflammatory genes repressed CHK2-YBX1&YBX3 hub. Targeting one hub proteins, inhibitor SU056 led degradation this antigen presentation specific proliferation. Further, combination ICB models. Collectively, findings reveal mechanism mediated proteins. Therefore, targeting immune checkpoint blockade therapies gliomas warranted.

Язык: Английский

---

Pathways and Molecular Mechanisms Governing LDL Receptor Regulation

Circulation Research, Год журнала: 2025, Номер 136(8), С. 902 - 919

Опубликована: Апрель 10, 2025

Clearance of circulating plasma LDL (low-density lipoprotein) cholesterol by the liver requires hepatic LDLR lipoprotein receptor). Complete absence functional manifests in severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Since discovery 50 years ago Brown Goldstein, all approved lipid-lowering medications have been aimed at increasing abundance availability on surface hepatocytes to promote removal particles from circulation. As such a critical regulator cellular cholesterol, it is not surprising that activity tightly regulated. Despite over half century’s worth study, there are still many facets biology remain unexplored. This review will focus pathways regulate emerging concepts biology.

Язык: Английский

---

RNA-Binding Proteins in the Regulation of Adipogenesis and Adipose Function

Cells, Год журнала: 2022, Номер 11(15), С. 2357 - 2357

Опубликована: Июль 31, 2022

The obesity epidemic represents a critical public health issue worldwide, as it is vital risk factor for many diseases, including type 2 diabetes (T2D) and cardiovascular disease. Obesity complex disease involving excessive fat accumulation. Proper adipose tissue accumulation function are highly transcriptional regulated by genes. Recent studies have discovered that post-transcriptional regulation, mainly mediated RNA-binding proteins (RBPs), also plays crucial role. In the lifetime of RNA, bound various RBPs determine every step RNA metabolism, from processing to alternative splicing, nucleus export, rate translation, finally decay. humans, predicted account more than 10% based on presence domains. However, only very few been studied in tissue. primary aim this paper provide an overview adipogenesis function. Specifically, following best-characterized will be discussed, HuR, PSPC1, Sam68, RBM4, Ybx1, Ybx2, IGF2BP2, KSRP. Characterization these increase our understanding regulatory mechanisms clues etiology pathology adipose-tissue-related diseases.

Язык: Английский

---

Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology

EBioMedicine, Год журнала: 2022, Номер 85, С. 104290 - 104290

Опубликована: Сен. 29, 2022

BackgroundEssential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic arms and, in some patients, involving other body regions (e.g., head, voice). Genetic studies suggest that ET is genetically heterogeneous.MethodsWe analyzed whole genome sequence data (WGS) generated on 104 multi-generational white families with European ancestry affected ET. Genome-wide parametric linkage and association scans were using adjusted logistic regression models through application Pseudomarker software. To investigate additional contribution rare variants familial ET, we also performed an aggregate variant non-parametric (NPL) analysis collapsed haplotype method implemented CHP-NPL software.FindingsParametric identified several loci significant evidence (HLOD ≥3.6). Among gene within strongest peaks BTC (4q13.3, HLOD=4.53), N6AMT1 (21q21.3, HLOD=4.31), PCDH9 (13q21.32, HLOD=4.21), EYA1 (8q13.3, HLOD=4.04), RBFOX1 (16p13.3, HLOD=4.02), MAPT (17q21.31, HLOD=3.99) SCARB2 (4q21.1, HLOD=3.65). fifteen genes (LOD ≥3.8). These include TUBB2A, VPS33B, STEAP1B, SPINK5, ZRANB1, TBC1D3C, PDPR, NPY4R, ETS2, ZNF736, SPATA21, ARL17A, PZP, BLK CCDC94. In family contributing to peak chromosome 16p13.3, likely pathogenic heterozygous canonical splice acceptor exon 2 (ENST00000547372; c.4-2A>G), co-segregated phenotype family.InterpretationLinkage analyses WGS novel candidate genes, which are implicated four major pathways 1) epidermal growth factor receptor-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-AKT serine/threonine kinase 1 (EGFR-PI3K-AKT) Mitogen-activated protein Kinase (ERK) pathways, 2) Reactive oxygen species (ROS) DNA repair, 3) gamma-aminobutyric acid-ergic (GABAergic) system 4) RNA binding regulation processes. Our study provides for possible overlap genetic architecture disease, cancer aging. The can be prioritized future functional studies.FundingNational Institutes Health, NINDS, NS073872 (USA) NIA AG058131(USA).

Язык: Английский

---