Biology subjects

Song, X.

Publications and source records attributed to Song, X..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas

Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell carcinomas (LSCCs). Our in vitro experiments using 2D human cancer cell lines as well as 3D murine and patient derived organoids treated with two inhibitors of the EZH2 plus interferon-{gamma} (IFN{gamma}) showed that EZH2 inhibition leads to expression of both major histocompatibility complex class I and II (MHCI/II) expression at both the mRNA and protein levels. ChIP-sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Further, we demonstrate strong tumor control in models of both autochthonous and syngeneic LSCC treated with anti-PD1 immunotherapy with EZH2 inhibition. Single-cell RNA sequencing and immune cell profiling demonstrated phenotypic changes towards more tumor suppressive phenotypes in EZH2 inhibitor treated tumors. These results indicate that this therapeutic modality could increase ICI responses in patients undergoing treatment for LSCC.

cancer biology↗

bioRxiv2023

Roles of Lipopolysaccharide Glycosyltransferases in Maintenance of Helicobacter pylori Morphology, Cell Wall Permeability, and Antimicobial Susceptibilities

Helicobacter pylori unique lipopolysaccharide structure is essential in maintaining the cell envelop integrity and renders the bacterium natural resistance to cationic antimicrobial peptides (CAMPs). Our group has recently elucidated the complete set of LPS glycosyltransferase genes in H. pylori reference strain G27. Here, with a series of 8 systematically constructed LPS glycosyltransferase gene mutants (G27{Delta}HP1578, G27{Delta}HP1283, G27{Delta}HP0159, G27{Delta}HP0479, G27{Delta}HP0102, G27{Delta}wecA, G27{Delta}HP1284 and G27{Delta}HP1191), we investigated the roles of H. pylori LPS glycosyltransferases in maintenance of cell morphology, cell wall permeability, and antimicrobial susceptibilities. We demonstrated that deletion of these LPS glycosyltransferase genes did not interfere with bacterial cell wall permeability, but resulted in significant morphological changes (coccoid, coiled "c"-shape, and irregular shapes) after 48 h growth as compared to the rod-like cell shape of the wild-type strain. Moreover, as compared with the wild-type, none of the LPS mutants had altered susceptibility against clarithromycin, levofloxacin, amoxicillin, tetracycline, and metronidazole. However, the deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, our findings suggest that the LPS glycosyltransferases play critical roles in the maintenance of the typical spiral morphology of H. pylori, as well as resistance to CAMPs and rifampicin. The LPS glycosyltransferases could be promising targets for developing novel anti-H. pylori drugs. ImportanceH. pylori typical helical morphology, cell wall integrity, as well as resistance to cationic CAMPs and antimicrobials are significant factors for its long-term colonization and persistent infection in human gastric mucosa. Our results show that each of the 8 LPS glycosyltransferase genes (HP1578, HP1283, HP0159, HP0479, HP0102, wecA, HP1284 and HP1191) deletion did not interfere with bacterial cell wall permeability, but resulted in significant loss of H. pylori typical helical shape. Furthermore, deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, we believe that the LPS glycosyltransferases are good targets for developing novel anti-H. pylori drugs.

microbiology↗

bioRxiv2023

Spatial transcriptome of developmental mouse brain reveals temporal dynamics of gene expressions and heterogeneity of the claustrum

During the development of the mammalian cerebral cortex, numerous neurons are arranged in a six-layer structure with an inside-out fashion to form the neocortex and wire neural circuits. This process includes cell proliferation, differentiation, migration, and maturation, supported by precise genetic regulation. To understand this sequence of processes at the cellular and molecular levels, it is necessary to characterize the fundamental anatomical structures by gene expression. However, markers established in the adult brain sometimes behave differently in the fetal brain, actively changing during development. Spatial transcriptomes yield genome-wide gene expression profiles from each spot patterned on tissue sections, capturing RNA molecules from fresh-frozen sections and enabling sequencing analysis while preserving spatial information. However, a deeper understanding of this data requires computational estimation, including integration with single-cell transcriptome data and aggregation of spots on the single-cell cluster level. The application of such analysis to biomarker discovery has only begun recently, and its application to the developing fetal brain is largely unexplored. In this study, we performed a spatial transcriptome analysis of the developing mouse brain to investigate the spatiotemporal regulation of gene expression during development. Using these data, we conducted an integrated study with publicly available mouse data sets, the adult brains spatial transcriptome, and the fetal brains single-cell transcriptome. Our data-driven analysis identified novel molecular markers of the choroid plexus, piriform cortex, thalamus, and claustrum. In addition, we revealed that the internal structure of the embryonic claustrum is composed of heterogeneous cell populations.

developmental biology↗

bioRxiv2023

An integrated map of genetic variation from 1,062 wheat genomes

The construction of a high-quality wheat genome variation map is important to wheat genetic studies and breeding. In this study, we developed the second-generation whole-genome genetic variation map of wheat (VMap 2.0) by integrating whole-genome sequencing data of 1,062 diverse wheat accessions from 20 species/subspecies. VMap 2.0 contains 195.96 million single nucleotide polymorphisms (SNPs), 2.22 million insertions, and 4.72 million deletions, achieving a high density of variation map in which one variant exists in every 73 base pairs on average. By systematically analyzing the phylogenetic relationships and genetic diversity of tetraploid wheat, hexaploid wheat, and diploid goatgrass (Aegilops tauschii), we found that the genetic diversity of wild emmer wheat was 2.4 times higher than that of common wheat. In contrast, the genetic diversity of diploid goatgrass is 7.8 times higher than the D subgenome of hexaploid wheat. With the high-density genetic variations, VMap 2.0 is anticipated to facilitate high-resolution trait dissection and expedite prediction-based breeding of wheat.

genomics↗

bioRxiv2023

Protein supersaturation powers innate immune signaling

How minute pathogenic signals trigger decisive immune responses is a fundamental question in biology. Classical signaling often relies on ATP-driven enzymatic cascades, but innate immunity frequently employs death fold domain (DFD) self-assembly. The energetic basis of this assembly is unknown. Here, we show that specific DFDs function as energy reservoirs through metastable supersaturation. Characterizing all 109 human DFDs, we identified sequence-encoded nucleation barriers specifically in the central adaptors of inflammatory signalosomes, allowing them to accumulate far above their saturation concentration while remaining soluble and poised for activation. We demonstrate that the inflammasome adaptor ASC is constitutively supersaturated in vivo, retaining energy that powers on-demand cell death. Swapping a non-supersaturable DFD in the apoptosome with a supersaturable one sensitized cells to sublethal stimuli. Mapping all DFD nucleating interactions revealed that supersaturated adaptors are triggered to polymerize specifically by other DFDs in their respective pathways, limiting potentially deleterious crosstalk. Across human cell types, adaptor supersaturation strongly correlates with cell turnover, implicating this thermodynamic principle in the trade-off between immunity and longevity. Profiling homologues from fish and sponge, we find nucleation barriers to be conserved across metazoa. These findings reveal DFD adaptors as biological phase change materials in thermal batteries to power cellular life-or-death decisions on demand.

immunology↗

bioRxiv2023

Long-B prokaryotic Argonaute systems employ various effectors to confer immunity via abortive infection

Argonaute proteins (Agos) bind short nucleic acids as guides and are directed by them to recognize target complementary nucleic acids. Prokaryotic Agos (pAgos) are extremely diverse, with potential functions in microbial defense. The functions and mechanisms of a group of full-length yet inactive pAgos, long-B pAgos, remain enigmatic. Here, we show that most long-B pAgos constitute cell suicide systems together with their various associated proteins, including nucleases, Sir2-domain-containing proteins and trans-membrane proteins, respectively. Among them, the long-B pAgo-nuclease system utilizes an RNA-programmed and target-recognition-activated collateral DNA cleavage activity to sense invaders and kill the infected cells. This results in depletion of the invading plasmid from the cell population. Together, our data indicate that the long-B pAgo systems induce cell death with various effector proteins after recognition of invading nucleic acids, corresponding to an immune response via abortive infection.

microbiology↗

bioRxiv2023

Spatial transcriptomic atlas of shoot organogenesis in tomato callus

Callus is a reprogrammed transitional cell mass during plant regeneration. Pluripotent callus cells develop into fertile shoots through de novo shoot organogenesis. This study represents a pioneering effort in exploring the spatial transcriptome of tomato callus during shoot regeneration, using technologies including BGI Stereo-seq, BMKMANU S1000, and 10x Visium. The results indicate that the callus comprises highly heterogeneous cells, classified into various cell types based on spatial gene expression and histological observation, including epidermis, shoot primordium, vascular tissue, inner callus, and outgrowth shoots. The developmental trajectories from shoot primordium to outgrowth shoot are traced, and vascular tissue development is characterized. The single-cell resolution spatial approach reveals the origin of shoot primordia from the sub-epidermis. The spatial full length RNA sequencing shows high incompletely spliced (IS) ratios in the shoot primordium cells. These findings enhance our knowledge of plant organogenesis and highlight the significance of spatial biology in plant research.

cell biology↗

bioRxiv2023

Microbiome induced complement synthesized in the gut protects against enteric infections

Canonically, complement is a serum-based host defense system that protects against systemic microbial invasion. Little is known about the production and function of complement components on mucosal surfaces. Here we show gut complement component 3 (C3), central to complement function, is regulated by the composition of the microbiota in healthy humans and mice, leading to host-specific gut C3 levels. Stromal cells in intestinal lymphoid follicles (LFs) are the predominant source of intestinal C3. During enteric infection with Citrobacter rodentium or enterohemorrhagic Escherichia coli, luminal C3 levels increase significantly and are required for protection. C. rodentium is remarkably more invasive to the gut epithelium of C3-deficient mice than of wild-type mice. In the gut, C3-mediated phagocytosis of C. rodentium functions to clear pathogens. Our study reveals that variations in gut microbiota determine individuals intestinal mucosal C3 levels, dominantly produced by LF stromal cells, which directly correlate with protection against enteric infection. HighlightsO_LIGut complement component 3 (C3) is induced by the microbiome in healthy humans and mice at a microbiota-specific level. C_LIO_LIGut stromal cells located in intestinal lymphoid follicles are a major source of luminal C3 C_LIO_LIDuring enteric infections with Citrobacter rodentium or enterohemorrhagic Escherichia coli, gut luminal C3 levels increase and are required for protection. C_LIO_LIC. rodentium is significantly more invasive of the gut epithelium in C3-deficient mice when compared to WT mice. C_LIO_LIIn the gut, C3-mediated opsonophagocytosis of C. rodentium functions to clear pathogens. C_LI

immunology↗

bioRxiv2023

Single-cell transcriptomic landscape deciphers novel olfactory neuroblastoma subtypes and intratumoral heterogeneity

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor known to originate from the olfactory epithelial. The complex tumor ecosystem of this pathology remained unclear. Here, we explored the cellular components with ONB tumors based on scRNA profiles of 96,325 single-cells derived from 10 tumors and 1 olfactory mucosa sample. We discovered 11 major cell types, including 6 immune cell, 3 stromal cell subtypes and epithelial cluster in the tumor microenvironment (TME), and identified 5 common expression programs from malignant epithelial cells. We analyzed subclusters of TME and the interactions among different cell types in the TME. An innovative three-classification of ONB was established via scRNA analysis. Markers for categorizing tumor samples into new subtypes were elucidated. Different responses towards certain chemotherapy regimens could be inferred according to the molecular features of three tumor types. Relative abundance of immunosuppressive TAMs indicated the benefits of immunotherapies targeting myeloid cells.

cancer biology↗

bioRxiv2023

A chemical probe to modulate human GID4 Pro/N-degron interactions

The CTLH complex is a multi-subunit ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via the substrate receptor GID4. Recently, focus has turned to this complex as a potential mediator of targeted protein degradation, but the role GID4-mediated substrate ubiquitylation and proteasomal degradation plays in humans has thus far remained unclear. Here, we report PFI-7, a potent, selective, and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation enabled the identification of dozens of endogenous GID4-interacting proteins that bind via the GID4 substrate binding pocket, only a subset of which possess canonical Pro/N-degron sequences. GID4 interactors are enriched for nuclear and nucleolar proteins including RNA helicases. GID4 antagonism by PFI-7 altered protein levels of several proteins including RNA helicases as measured by label-free quantitative proteomics, defining proteins that are regulated by GID4 and the CTLH complex in humans. Interactions with GID4 via Pro/N-degron pathway did not result in proteasomal degradation, demonstrating that CTLH interactors are regulated through a combination of degradative and non-degradative functions. The lack of degradation of GID4 interactors highlights potential challenges in utilizing GID4-recruiting bifunctional molecules for targeted protein degradation. Going forward, PFI-7 will be a valuable research tool for defining CTLH complex biology and honing targeted protein degradation strategies.

molecular biology↗

bioRxiv2022

SGC-CLK-1 (CAF-170) a chemical probe for the Cdc2-Like kinases CLK1, CLK2, and CLK4

Small molecule modulators are important tools to study both basic biology and the complex signaling of protein kinases. The cdc2-like kinases (CLK) are a family of four kinases that have garnered recent interest for their involvement in a diverse set of diseases such as neurodegeneration, autoimmunity, and many cancers. Targeted medicinal chemistry around a CLK inhibitor hit identified through screening of a kinase inhibitor set against a large panel of kinases allowed us to identify a potent and selective inhibitor of CLK1, 2 and 4. Here, we present the synthesis, selectivity, and potential binding site of this compound - SGC-CLK-1. We further show CLK2 has the highest binding affinity, and high CLK2 expression correlates with a lower IC50 in a screen of multiple cancer cell lines. Finally, we show that SGC-CLK-1 not only reduces serine arginine rich (SR) protein phosphorylation, but also alters SR protein and CLK2 subcellular localization in a reversible way. Therefore, we anticipate that this compound will be a valuable tool for increasing our understanding of CLKs and their targets, SR proteins, at the level of phosphorylation and subcellular localization.

cancer biology↗

bioRxiv2022

Methyl Halide Transferase-Based Gas Reporters for Quantification of Filamentous Bacteria in Microdroplet Emulsions

The application of microfluidic techniques in experimental and environmental studies is a rapidly emerging field. Water-in-oil microdroplets can serve readily as controllable micro-vessels for studies that require spatial structure. In many applications, it is useful to monitor cell growth without breaking or disrupting the microdroplets. To this end, optical reporters based on color, fluorescence, or luminescence have been developed. However, optical reporters suffer from limitations when used in microdroplets such as inaccurate readings due to strong background interference or limited sensitivity during early growth stages. In addition, optical detection is typically not amenable to filamentous or biofilm-producing organisms that have significant non-linear changes in opacity and light scattering during growth. To overcome such limitations, we show that volatile methyl halide gases produced by reporter cells expressing a methyl halide transferase (MHT) can serve as an alternative non-optical detection approach suitable for microdroplets. In this study, an MHT-labeled Streptomyces venezuelae reporter strain was constructed and characterized. Protocols were established for the encapsulation and incubation of S. venezuelae in microdroplets. We observed the complete life cycle for S. venezuelae including the vegetative expansion of mycelia, mycelial fragmentation, and late-stage sporulation. Methyl bromide (MeBr) production was detected by gas chromatography-mass spectrometry (GC-MS) from S. venezuelae gas reporters incubated in either liquid suspension or microdroplets and used to quantitatively estimate bacterial density. Overall, using MeBr production as a means of quantifying bacterial growth provided a 100-1000 fold increase in sensitivity over optical or fluorescence measurements of a comparable reporter strain expressing fluorescent proteins. ImportanceQuantitative measurement of bacterial growth in microdroplets in situ is desirable but challenging. Current optical reporter systems suffer from limitations when applied to filamentous or biofilm-producing organisms. In this study, we demonstrate that volatile methyl halide gas production can serve as a quantitative non-optical growth assay for filamentous bacteria encapsulated in microdroplets. We constructed an S. venezuelae gas reporter strain and observed a complete life cycle for encapsulated S. venezuelae in microdroplets, establishing microdroplets as an alternative growth environment for Streptomyces spp. that can provide spatial structure. We detected MeBr production from both liquid suspension and microdroplets with a 100-1000 fold increase in signal-to-noise ratio compared to optical assays. Importantly, we could reliably detect bacteria with densities down to 106 CFU/mL. The combination of quantitative gas reporting and microdroplet systems provides a valuable approach to studying fastidious organisms that require spatial structure such as those found typically in soils. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/519239v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@f77645org.highwire.dtl.DTLVardef@75b4b6org.highwire.dtl.DTLVardef@1ab4d47org.highwire.dtl.DTLVardef@15e8de5_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Repurposing clemastine to target glioblastoma cell stemness

Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearing PDGFRA amplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that Emopamil binding protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is essential for BTIC propagation and a target that mediates the suppressive effects of clemastine. Finally, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment. Collectively, these results identify pathways essential for maintaining the stemness and progenitor features of GBMs, uncover BTIC dependency on EBP, and suggest that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment.

cancer biology↗

bioRxiv2022

Fear of missing out (FOMO) associates with reduced cortical thickness in core regions of the posterior default mode network and higher levels of problematic smartphone and social media use

Fear of missing out (FOMO) promotes the desire or urge to stay continuously connected with a social reference group and updated on their activities, which may result in escalating and potentially addictive smartphone and social media use. The present study aimed to determine whether the neurobiological basis of FOMO encompasses core regions of the reward or social brain, and the associations with the level of problematic smartphone or social media use. We capitalized on a dimensional neuroimaging approach to examine cortical thickness and subcortical volume associations in a comparably large sample of healthy young individuals (n = 167). Meta-analytic network and behavioral decoding were employed to further characterize the identified regions. Higher levels of FOMO associated with lower cortical thickness in the precuneus. In contrast, no associations between FOMO and variations in striatal morphology were observed. Meta-analysis decoding revealed that the identified precuneus region exhibited a strong functional interaction with the default mode network (DMN) engaged in social cognitive and self-referential domains. Together the present findings suggest that individual variations in FOMO are associated with the brain structural architecture of the right precuneus, a core hub within a large-scale functional network resembling the DMN involved in social and self-referential processes. FOMO may promote escalating social media and smartphone use via social and self-referential processes rather than reward-related processes per se.

neuroscience↗

bioRxiv2022

Damage dynamics in single E. coli and the role of chance in the timing of cell death

Genetically identical cells in the same stressful condition die at different times. The origin of this stochasticity is unclear; it may arise from different initial conditions that affect the time of demise, or from a stochastic damage accumulation mechanism that erases the initial conditions and instead amplifies noise to generate different lifespans. To address this requires measuring damage dynamics in individual cells over the lifespan, but this has rarely been achieved. Here, we used a microfluidic device to measure membrane damage in 648 carbon-starved E. coli cells at high temporal resolution. We find that initial conditions of damage, size or cell-cycle phase do not explain most of the lifespan variation. Instead, the data points to a stochastic mechanism in which noise is amplified by a rising production of damage that saturates its own removal. Surprisingly, the relative variation in damage drops with age: cells become more similar to each other in terms of relative damage, indicating increasing determinism with age. Thus, chance erases initial conditions and then gives way to increasingly deterministic dynamics that dominate the lifespan distribution.

systems biology↗

bioRxiv2022

Brevicidine, a bacterial non-ribosomally produced cyclic antimicrobial lipopeptide with a unique modus operandi

Due to the accelerated appearance of antibiotic-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately-needed. Brevicidine, a bacterial non-ribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMR Enterobacteriaceae pathogens, with a MIC value ranging between 0.5M (0.8mg/L) and 2M (3.0mg/L). In addition, brevicidine showed potent anti-biofilm activity against the Enterobacteriaceae pathogens, with same 100% inhibition and 100% eradication concentration of 4M (6.1mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity via interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including inhibition of adenosine triphosphate synthesis, inhibits the dehydrogenation of nicotinamide adenine dinucleotides, accumulation of reactive oxygen species in bacteria, and inhibition of protein synthesis. Lastly, brevicidine showed a good therapeutic effect in a mouse peritonitis-sepsis model. Our findings pave the way for further research on clinical applications of brevicidine, to combat the prevalent infections caused by AMR Gram-negative pathogens worldwide.

microbiology↗

bioRxiv2022

Exploring causal effects of smoking and alcohol related lifestyle factors on self-report tiredness: a Mendelian randomization study

Self-reported tiredness or low energy, often referred to as fatigue, has been linked to lifestyle factors, although data from randomized-controlled trials are lacking. We investigate whether modifiable lifestyle factors including smoking and alcohol intake related exposures (SAIEs) are causal factors for fatigue using Mendelian randomization (MR). A two-sample MR study was performed by using genome-wide association summary results from UK Biobank (UKBB), and each of the sample size is more than 100,000. We used the inverse variance weighted method, and sensitivity analyses (MR Egger, weighted median and penalized median estimators) to account for pleiotropy. The two-sample MR analyses showed inverse causal effect of never-smoking status and positive effect of current smoking status on the risk of fatigue. Similarly, genetically predicted alcoholic intake was positively associated with fatigue. The results were consistent across the different MR methods. Our Mendelian randomization analyses do support that the cessation of smoking and alcohol can decrease the risk of fatigue, and limit alcohol intake frequency can also reduce the risk. Author summaryMany lifestyle factors have been associated with the risk of fatigue, but we cannot ascertain the causality between lifestyle factors and the risk of fatigue; whether the modification of lifestyles will reduce the risk. Another challenge is that fatigue is usually caused by various physiological and pathological factors, so most epidemiological data which examined risk factor modification have not studied the relationship between modifiable risk factors and self-reported tiredness in extensive conditions. SAIEs are the ones of the most influential lifestyle factors for human health and wellbeing. We performed MR analyses to estimate the causal effect of SAIEs on fatigue. In our study, we initially identified genetic variants which are significantly associated with SAIEs. We found SAIEs are causally involved in fatigue. The results could be extremely useful in the context of lifestyle - health relationships.

genomics↗

bioRxiv2022

STAT3 promotes RNA polymerase III-directed transcription by controlling the miR-106a-5p/TP73 axis

AbstractsDeregulation of Pol III products causes a range of diseases, including neural diseases and cancers. However, the pathways and factors that control Pol III-directed transcription have yet to be elucidated. Here, we show that STAT3 positively regulates the activities of Pol III-dependent transcription and cancer cell growth. RNA-seq analysis revealed that STAT3 inhibits the expression of TP73, a member of the p53 family. We found that TP73 is not only required for the regulation of Pol III-directed transcription mediated by STAT3 but also independently suppresses the synthesis of Pol III products. Mechanistically, TP73 can disrupt the assembly of TFIIIB subunits and inhibit their occupancies at Pol III target loci by interacting with TFIIB subunit TBP. MiR-106a-5p can activate Pol III-directed transcription by targeting the TP73 mRNA 3 UTR to reduce TP 73 expression. We show that STAT3 activates the expression of miR-106a-5p by binding to the microRNA promoter, indicating that miR-106a-5p links STAT3 to TP73 and Pol III transcription. Collectively, these findings indicate that STAT3 functions as a positive regulator in Pol III-directed transcription by controlling the miR-106a-5p/TP73 axis.

molecular biology↗