Biology subjects

B. Toth, B.

Publications and source records attributed to B. Toth, B..

3 recordsLinked to original sources

bioRxiv2024

Deciphering Species-Specific and Conserved Regulation of Human UCP1 Gene Expression: Insights from Predicted Homeodomain Family Transcription Factor Binding Sites

Adipocyte thermogenesis is a promising target for treating metabolic disorders, but its regulatory mechanisms remain unclear. This study investigates transcription factors (TFs) and regulatory elements that may control the human UCP1 gene, which is essential for thermogenesis and the formation of the adipocyte phenotype. Using the Eukaryota Promoter Database, we performed computational analyses of the UCP1, UCP2 and UCP3 promoter sequences in humans, mice and rats to identify conserved and species-specific elements. We also used transcriptome data from human neck-derived adipocytes and databases (Contra v3, ChiPBase, TFlink, AdipoNet, ISMARA, etc.) to narrow potential regulatory TFs. Our results show that mouse and rat UCP1 enhancers lack large segments, primarily due to the insertion of repetitive elements that are already lost in some clades. We identified key TFs such as PPARA, PPARG, THR, RARE, RXR, JUN, TFAP2 and SREBF1 as general regulators of UCPs. Additionally, human-specific UCP1 regulatory hotspots (e.g. 5-TCTAATTAGA-3) recognised by homeodomain TFs (e.g. EN1, PAX4, HOXA5 and PRRX2) and NFIL3 were detected. Phylogenetically conserved regulatory elements suggest common TFs in human UCP1 paralogues (MAX, MYCN, MNT, HES1) and cross-species (POU6F1). These results improve our understanding of thermogenic adipocyte development and provide new therapeutic targets for metabolic diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/594487v2_ufig1.gif" ALT="Figure 1"> View larger version (82K): org.highwire.dtl.DTLVardef@1fe65a3org.highwire.dtl.DTLVardef@c2c6e5org.highwire.dtl.DTLVardef@1900abborg.highwire.dtl.DTLVardef@1b09883_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2021

Irisin stimulates the release of CXCL1 from differentiating human subcutaneous and deep-neck derived adipocytes via upregulation of NFκB pathway

Thermogenic brown and beige adipocytes play an important role in combating obesity. Recent studies in rodents and humans have indicated that these adipocytes release cytokines, termed "batokines". Irisin was discovered as a polypeptide regulator of beige adipocytes released by myocytes, primarily during exercise. We performed global RNA sequencing on adipocytes derived from human subcutaneous and deep-neck precursors, which were differentiated in the presence or absence of irisin. Irisin did not exert an effect on the expression of characteristic thermogenic genes, while upregulated genes belonging to various cytokine signaling pathways. Out of the several upregulated cytokines, CXCL1, the highest upregulated, was released throughout the entire differentiation period, and predominantly by differentiated adipocytes. Deep-neck area tissue biopsies also showed a significant release of CXCL1 during 24 hours irisin treatment. Gene expression data indicated upregulation of the NF[kcy]B pathway upon irisin treatment, which was validated by an increase of p50 and decrease of I[kcy]B protein level, respectively. Continuous blocking of the NF{kappa}B pathway, using a cell permeable inhibitor of NF{kappa}B nuclear translocation, significantly reduced CXCL1 release. The released CXCL1 exerted a positive effect on the adhesion of endothelial cells. Together, our findings demonstrate that irisin stimulates the release of a novel "batokine", CXCL1, via upregulation of NF{kappa}B pathway in neck area derived adipocytes, which might play an important role in improving tissue vascularization.

cell biology↗

bioRxiv2021

Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes

Recently, ProFAT and BATLAS scores have been offered to determine thermogenic status of adipocytes using expression pattern of brown and white marker-genes. In this work, we investigated the functional context of these genes. Although the two meta-analyses based marker-gene lists have little overlap, their enriched pathways show strong coincides suggesting they may better characterize adipocytes. We demonstrate that functional genomics of the annotated genes in common pathways enables an extended analysis of thermogenesis regulation, generates testable hypotheses supported by experimental results in human adipocytes with different browning potential and may lead to more global conclusions than single-state studies. Our results imply that different biological processes shape brown and white adipocytes with presumed transitional states. We propose that the thermogenic adipocyte phenotype require both repression of whitening and induction of browning. These simultaneous actions and hitherto unnoticed regulatory modules, such as the exemplified HIF1A that may directly act at UCP1 promoter, can set new direction in obesity research. HighlightsO_LIIntegrated pathways better characterize brown adipocytes than marker-genes C_LIO_LIDifferent processes shape the brown and white adipocyte phenotypes C_LIO_LIThermogenic phenotype may require simultaneous repression of whitening and induction of browning C_LIO_LIProtein network analyses reveals unnoticed regulatory modules of adipocyte phenotype C_LIO_LIHIF1A may regulate thermogenesis by direct control of UCP1 gene-expression C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/428057v2_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@b4c730org.highwire.dtl.DTLVardef@813b58org.highwire.dtl.DTLVardef@5f3398org.highwire.dtl.DTLVardef@344eb5_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗