Biology subjects

Sultanov, R. I.

Publications and source records attributed to Sultanov, R. I..

4 recordsLinked to original sources

bioRxiv2025

A trans-acting enhancer lncRNA modulates androgen-dependent gene expression via sequence-specific interaction with the Androgen Receptor

BackgroundEnhancer RNAs (eRNAs) have been shown to modulate the transcriptional landscape of prostate cancer (PCa). The Androgen Receptor (AR), a well-known modulator of eRNA expression, contains an RNA-binding region that interacts with RNA molecules in a sequence-specific manner. However, there is currently no evidence that AR forms complexes with eRNAs to regulate gene expression. MethodsTo explore the eRNA-AR interactome, we reanalyzed publicly available RNA-seq, ChIP-seq, and AR-RIP-seq data from prostate cancer cell lines to identify a single long non-coding eRNA that interacts with AR (ARA-elncRNA1). Using linear regression, we identified genomic regions where AR occupancy is associated with the expression level of ARA-elncRNA1. We further demonstrated that this eRNA recruits AR to YY1-mediated enhancer-promoter loops, stabilizing these interactions. A series of experiments, including RIP-qPCR, ChIP-qPCR, and EMSA, were conducted to validate the proposed model. Finally, we investigated the role of ARA-elncRNA1 in prostate cancer cells survival. ResultsWe confirmed the sequence-specific interaction between AR and ARA-elncRNA1. This eRNA not only regulates AR occupancy at the promoters of several AR-dependent genes but also protects AR from proteasomal degradation. The AR:ARA-elncRNA1 complex interacts with YY1 and influences enhancer-promoter looping. Additionally, ARA-elncRNA1 was found to inhibit the proliferation of prostate cancer (PCa) cells in vitro and expression level of lncRNA was associated with a lower Gleason score. ConclusionsOur findings revealed the existence of an eRNA that directly binds to AR and regulates, in trans, the expression of several AR-dependent genes. We demonstrated that eRNAs can not only interact with AR but also modulate chromatin structure. These insights shed new light on the functional roles of eRNAs and their contribution to cancer development.

cancer biology↗

bioRxiv2024

Large MAF Transcription Factors Reawaken Evolutionarily Dormant Fast-Glycolytic Type IIb Myofibers in Human Skeletal Muscle

Small mammals rely on type IIb myofibers, expressing the fastest myosin IIb (encoded by MYH4), for rapid muscle contraction. In contrast, larger mammals, including humans, show reduced or absent MYH4 expression and type IIb myofibers, favoring slower-contracting myofibers. The evolutionary mechanisms underlying this shift remain unclear. Here, we identify large MAF transcription factors (MAFA, MAFB, MAF) as key regulators of MYH4 expression in large mammals, including human and bovine. Overexpression of large MAFs induces MYH4 expression and enhances glycolytic capacity in human myotubes, supported by RNA-seq and metabolic flux analyses. RNA-seq of human muscle biopsies reveals a positive correlation between MAFA, MAF, and MYH4 expression, with these genes elevated in power-trained individuals. These findings reveal a conserved mechanism across mammals, showing that large MAFs can induce type IIb myofibers even in humans, with potential applications for enhancing athletic performance and addressing age-related muscle weakness associated with the loss of fast-twitch myofibers.

cell biology↗

bioRxiv2022

Co-expression analysis reveals gene cluster associated with methylation of enhancers and chromosomal instability under TP63 and TRIM29 regulation

AO_SCPLOWBSTRACTC_SCPLOWProstate adenocarcinoma (PRAD) is the second most common cause of cancer-related deaths in men. PRAD is often characterized by DNA methylation variability and a high rate of large genomic rearrangements. To elucidate the reasons behind such high variance, we used weighted gene co-expression network analysis for integration RNA-seq, DNA methylation and copy number alterations data from The Cancer Genome Atlas PRAD. Our results show that only a single cluster of co-expressed genes is associated with genomic and epigenomic instability. Within this cluster, TP63 and TRIM29 are key transcription regulators. We revealed that TP63 regulates the level of enhancer methylation in prostate basal epithelium cells. TRIM29 forms a complex with TP63 and together regulate the expression of genes specific to the prostate basal epithelium. Moreover, TRIM29 binds DNA repair proteins and prevents formation of the TMPRSS2:ERG gene fusion typically observed in PRAD. Therefore, the study shows that TRIM29 and TP63 are important regulators maintaining the identity of the basal epithelium under physiological conditions. Finally, we uncover the role of TRIM29 in PRAD development.

systems biology↗

bioRxiv2019

DNA methylation across the genome in aged human skeletal muscle tissue and muscle stem cells: The role of HOX genes and physical activity

Skeletal muscle tissue demonstrates global hypermethylation with aging. However, methylome changes across the time-course of differentiation in aged human muscle derived stem cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 {+/-} 4.4 years) and aged (83 {+/-} 4 years) human skeletal muscle and that of young/aged muscle stem cells over several time points of differentiation (0, 72 hours, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged muscle stem cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alteration in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in the focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and isolated muscle stem cells, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle and tissue and stem cells (on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P). Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and muscle stem cells and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

physiology↗