Biology subjects

Xiao, Z.

Publications and source records attributed to Xiao, Z..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Replay-triggered Brain-wide Activation in Humans

The consolidation of discrete experiences into a coherent narrative shape our cognitive map, providing a structured mental representation of our experiences. Neural replay, by fostering crucial hippocampal-cortical dialogue, is thought to be pivotal in this process. However, the brain-wide engagement coinciding with replay bursts remains largely unexplored. In this study, by employing simultaneous EEG-fMRI, we capture both the spatial and temporal dynamics of replay. We find that during mental simulation, the strength of on-task replay, as detected via EEG, correlates with heightened fMRI activity in the hippocampus and medial prefrontal cortex. Intriguingly, increased replay strength also enhances the functional connectivity between the hippocampus and the default mode network, a set of brain regions key to representing cognitive map. Furthermore, during the post-learning resting state, we observed a positive association between increased task-related reactivation, hippocampal activity, and augmented connectivity to the entorhinal cortex. Our findings elucidate the neural mechanism of human replay in both time and space, providing novel insights into dynamics of replay and associated brain-wide activation.

neuroscience↗

bioRxiv2023

Reduced Reverse Replay in Anxious Individuals Impairs Reward Prediction

Understanding how we learn about the value and structure of our environment is central to neurocognitive theories of many psychiatric and neurological disorders. Learning processes have been extensively studied during performance of behavioural tasks (online learning) but less so in relation to "resting" (offline) states. A candidate mechanism for such offline learning is "replay," the sequential neural reactivation of past experiences. Notably, value-based learning is especially tied to replay unfolding in reverse order relative to the original experience ("backward replay"). Here, we demonstrate the utility of EEG-based neural decoding for investigating offline learning, and relate it to trait anxiety. Participants were first required to infer sequential relationships among task objects by using a learned rule to reorganise their visual experiences into distinct sequences. Afterwards, they observed that the final object in one of the sequences was associated with a monetary reward and then entered a post-value resting state. During this rest, we found evidence of backward replay for reward-linked object sequences. The strength of such replay was negatively associated with trait anxiety and positively predicted an increased behavioural preference for reward-predictive stimuli. We also found that high-trait-anxiety individuals showed inefficient credit assignment irrespective of reward magnitude, indicating that this effect does not merely reflect reduced reward sensitivity. Together, these findings suggest a potential aberrant replay mechanism during offline learning in individuals with high trait anxiety. More broadly, our approach illustrates the potential of EEG for measuring structured neural representations in vivo, with implications for studying cognition across a range of neuropsychiatric and neurological disorders.

neuroscience↗

bioRxiv2023

Generative artificial intelligence GPT-4 accelerates knowledge mining and machine learning for synthetic biology

Knowledge mining from synthetic biology journal articles for machine learning (ML) applications is a labor-intensive process. The development of natural language processing (NLP) tools, such as GPT-4, can accelerate the extraction of published information related to microbial performance under complex strain engineering and bioreactor conditions. As a proof of concept, we used GPT-4 to extract knowledge from 176 publications on two oleaginous yeasts (Yarrowia lipolytica and Rhodosporidium toruloides). After integration with a molecule inventory database, the outcome is a total of 2037 data instances and 28 features, which serve as machine learning inputs. The structured datasets enabled ML approaches (e.g., a random forest model) to predict Yarrowia fermentation titers with high accuracy (R2 of 0.86 for unseen test data). Via transfer learning, the trained model could also assess the production capability of the non-conventional yeast, R. toruloides, for which there are fewer published reports. This work demonstrated the potential of generative artificial intelligence to speed up information extraction from research articles, thereby improving design-build-test-learn (DBTL) cycles for commercial biomanufacturing development.

bioengineering↗

bioRxiv2023

Disruption of desmoplastic stroma overcomes restrictions to T cell extravasation, immune exclusion and immunosuppression in solid tumors

The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP+CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR and to anti-PD1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8+ T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma-and malignant cell-targeted therapies to be tested in clinical trials.

immunology↗

bioRxiv2023

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

Neurofunctional dysregulations in spatially discrete areas or isolated pathways have been suggested as neural markers for attention deficit hyperactivity disorder (ADHD). However, multiscale perspectives into the neurobiological underpins of ADHD spanning multiple biological systems remain sparse. This points to the need of multi-levels of analysis encompassing brain functional organization and its correlation with molecular and cell-specific transcriptional signatures are stressed. Here, we capitalized on diffusion mapping embedding model to derive the functional connectome gradient, and deployed multivariate partial least square (PLS) method to uncover the enrichment of neurotransmitomic, cellular and chromosomal connectome-transcriptional signatures of ADHD. Compared to typical control, ADHD children presented connectopic cortical perturbations in lateral orbito-frontal and superior temporal regions, which had also been validated in another independent sample. This gradient-derived variants in ADHD further aligned spatially with distributions of GABAA/BZ and 5-HT2A receptors and co-varied with genetic transcriptional expression. Cognitive decoding and gene-expression annotation showed the correlates of these variants in memory, emotional regulation and spatial attention. Moreover, the gradient-derived transcriptional signatures of ADHD exhibited enriched expression of oligodendrocyte precursors and endothelial cells, and were mainly involved as variants of chromosome 18, 19 and X. In conclusion, our findings bridged in-vivo neuroimging assessed functional brain organization patterns to a multi-level molecular pathway in ADHD, possibly shedding light on the interrelation of biological systems that may coalesce to the emergence of this disorder.

neuroscience↗

bioRxiv2023

GenBank genomics highlight the genomic features, genetic diversity and regulation of morphological, metabolic and disease-resistance traits in Nicotiana tabacum

Nicotiana tabacum is a model organism in plant molecular and pathogenic research and has significant potential in the production of biofuels and active pharmaceutical compounds in synthetic biology. Because of the large allotetraploid genome of tobacco, its genomic features, genetic diversity and genetic regulation of many complex traits remain unknown. In this study, we present a nearly complete chromosome-scale assembly of N. tabacum and provide evidence that homoeologous exchange between subgenomes and epigenetic remodelling are likely mechanisms of genome stabilization and subgenome coordination following polyploidization. By leveraging GenBank-scale sequencing and phenotyping data from 5196 lines, geography at the continent scale, rather than types assigned on the basis of curing crop practices, was found to be the most important correlate of genetic structure. Using 178 marker{square}trait associations detected in genome-wide association analysis, a reference genotype-to-phenotype map was built for 39 morphological, developmental, and disease-resistance traits. A novel gene, auxin response factor 9 (Arf9), associated with wider leaves after being knocked out, was fine-mapped to a single nucleotide polymorphism (SNP). This point mutation alters the translated amino acid from Ala203 to Pro203, likely preventing homodimer formation during DNA binding. Our analysis also revealed signatures of positive and polygenic selection for multiple traits during the process of selective breeding. Overall, this study demonstrated the power of leveraging GenBank genomics to gain insights into the genomic features, genetic diversity, and regulation of complex traits in N. tabacum, laying a foundation for future research on plant functional genomics, crop breeding, and the production of biopharmaceuticals and biofuels.

genetics↗

bioRxiv2023

Visualization and review of reads alignment on the graphical pan-genome with VAG

Recent advances in pangenomics have led to the rapid development of graph-based pangenomes that code genetic variant as nodes and edges preserve the contiguity of the sequence and structural variation between individuals. Data visualization is an essential component of genomic data analysis. However, the further application of the graph-based pangenome is still suffered from lacking bioinformatics tools to visualize graph format pangenomes and understand the reads alignment on graph pangenomes. In this research, we developed a novel bioinformatics platform, VAG (Visualizing read alignments in graph genomes), to overcome these challenges. VAG includes multifunctional modules integrated into a single command line and an online visualization platform supported through a web server. This tool can extract specific sequence regions from a graph pangenome and display read alignments on different paths of a graph pangenome. In addition, VAG provides population-level presence/absence variations frequency analysis and sequence path navigation to identify the population differentiation regions. To demonstrate the usage, we investigated genetic variations using a rice graph pangenome with population-level sequencing data to identify important genes and gene clusters underlying the indica-japonica differentiation with VAG. After investigating read alignments on the graph pangenome, we identified many false-positive alignments due to TE insertions. To reduce the impact of these misleading alignments, we developed a navigation module to determine and filter those false-positive alignments based on the pair-end alignment information. The utilization of mate-pair information in VAG provides a reliable reference for variation identification. Additionally, we developed a VAG web server to provide a user-friendly and interactive platform to visualize the read alignment data. VAG was also applied to SV discovery in the cucumber and soybean graph-based pangenome and details of VAG can be accessed by the following website (https://ricegenomichjx.xiaomy.net/VAG/sequenceextraction.php).

bioinformatics↗

bioRxiv2022

Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are highly resistant to reprogramming. There must be barriers that block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using a variety of oncogenic transgenes, and discovered transformed cell lines that remain compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed very early, whilst other lines seemed to progress through a normal-looking reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperactive epigenetic state in some of the transformed cells. This study reveals that the barriers underlying resistance to reprogramming vary between the different transformation methods. Key findingsO_LISomatic cell reprogramming of transformed cells is context-specific C_LIO_LIInhibition of MEK converts some cell lines to reprogramming-capable C_LIO_LITransformed cell lines are characterized by a hyperactive chromatin state C_LIO_LIMEK inhibition indirectly affects chromatin to enable reprogramming C_LI

cell biology↗

bioRxiv2022

A new polymodal gating model of the proton-activated chloride channel

The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we interrogated PAC channel gating using its unique bidirectional modulator C77304 as a pharmacological probe. C77304 activated the PAC channel by acting on its proton gating, while simultaneously inhibiting channel activity at higher doses, through interaction with two modulatory sites with different affinities and state-dependence. Excitingly, we revealed that PAC undergoes intrinsic proton gating-independent voltage activation, which was defined by an ion-flux gating mechanism. Scanning-mutagenesis and molecular dynamics simulation confirmed that E181, E257, and E261 in human PAC form the primary proton sensors, as alanine mutations eliminated the channels proton gating while sparing the voltage-dependent gating. This proton sensing mechanism was basically conserved among orthologous PAC channels. Collectively, our data unveils the polymodal gating and proton sensing mechanisms in the PAC channel which may inspire potential drug development.

neuroscience↗

bioRxiv2022

An intestinal sphingolipid promotes neuronal health across generations

Maternal diet and environment can influence the neuronal health of offspring. Here, we report that diet-induced intestinal sphingolipid biosynthesis reduces adult-onset neurodegeneration intergenerationally in Caenorhabditis elegans. Feeding C. elegans with ursolic acid (UA), a natural plant product, provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate (S1P) - a bioactive sphingolipid. S1P promotes neuronal health across generations by upregulating transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Intergenerational intestine-to-oocyte S1P transfer is essential for promoting neuronal health and is dependent on the lipoprotein yolk receptor RME-2 (Receptor-Mediated Endocytosis-2). Spatially regulating sphingolipid biosynthesis is critical, as inappropriate asah-1 neuronal expression causes developmental axon outgrowth defects. Our results reveal that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. One-Sentence SummaryAn intestinal lipid prevents neurodegeneration across generations.

neuroscience↗

bioRxiv2022

multiMiAT: An optimal microbiome-based association test for multicategory phenotypes

Microbes affect the metabolism, immunity, digestion and other aspects of the human body incessantly, and dysbiosis of the microbiome drives not only the occurrence but also the development of disease (i.e., multiple statuses of disease). Recently, microbiome-based association tests have been widely developed to detect the association between the microbiome and host phenotype. However, existing methods have not achieved satisfactory performance in testing the association between the microbiome and ordinal/nominal multicategory phenotypes (e.g., disease severity and tumor subtype). In this paper, we propose an optimal microbiome-based association test for multicategory phenotypes, namely, multiMiAT. Specifically, under the multinomial logit model framework, we first introduce a microbiome regression-based kernel association test (multiMiRKAT). As a data-driven optimal test, multiMiAT then integrates multiMiRKAT, score test and MiRKAT-MC to maintain excellent performance in diverse association patterns. Massive simulation experiments prove the excellent performance of our method. multiMiAT is also applied to real microbiome data experiments to detect the association between the gut microbiome and clinical statuses of colorectal cancer development and the association between the gut microbiome and diverse development statuses of Clostridium difficile infections.

genetics↗

bioRxiv2022

Distinct airway progenitor cells drive epithelial heterogeneity in the developing human lung

Recent advances using single cell genomic approaches have identified new epithelial cell types and uncovered cellular heterogeneity in the murine and human lung (1). Here, using scRNA-seq and microscopy we identify and describe a secretory-like cell that is enriched in the small airways of the developing human lung and identified by the unique co-expression of SCGB3A2/SFTPB/CFTR. To place these cells in the hierarchy of airway development, we apply a single cell barcode-based lineage tracing method track the fate of SCGB3A2/SFTPB/CFTR cells during airway organoid differentiation in vitro (2). Lineage tracing revealed that these cells have distinct developmental potential from basal cells, giving rise predominantly to pulmonary neuroendocrine cells (PNECs) and a subset of multiciliated cells distinguished by high C6 and low MUC16 expression. We conclude that SCGB3A2/SFTPB/CFTR cells act as a progenitor cell contributing to the cellular diversity and heterogeneity in the developing human airway. SIGNIFICANCE STATEMENTThe current study identifies a novel secretory cell type that is present predominantly in the small airway of the developing human lung. These secretory cells are defined by co-expression of SCGB3A2/SFTPB/CFTR, and functional studies show that this cell gives rise to pulmonary neuroendocrine cells and a sub-population of multiciliated cells, thereby leading to cellular heterogeneity.

developmental biology↗

bioRxiv2022

Stable iPSC-derived NKX2-1+ Lung Bud Tip Progenitor Organoids Give Rise to Airway and Alveolar Cell Types

Bud tip progenitors (BTPs) in the developing lung give rise to all epithelial cell types found in the airways and alveoli. The current work aimed to develop an iPSC organoid model enriched with stable NKX2-1+ BTP-like cells. Building on prior work, we optimized a directed differentiation paradigm to generate spheroids with robust NKX2-1 expression. Spheroids were expanded into organoids that possessed NKX2-1+/CPM+ BTP-like cells, which increased in number over time. Single cell RNA-sequencing analysis revealed a high degree of transcriptional similarity between induced BTPs (iBTPs) and in vivo BTPs. Using FACS, iBTPs can be purified and expanded as induced bud tip organoids (iBTO), which maintain an enriched population of bud tip progenitors. When iBTOs are directed to differentiate into airway or alveolar cell types using well-established methods, they give rise to organoids composed of organized airway or alveolar epithelium, respectively. Collectively, iBTOs are transcriptionally and functionally similar to in vivo BTPs, providing an important model to study human lung development and differentiation. SUMMARY STATEMENTiPSC-derived lung bud tip progenitors emerge in organoid culture, can be isolated and expanded, are transcriptionally similar to primary bud tip progenitors, and can differentiate into airway or alveolar organoids.

developmental biology↗

bioRxiv2022

The influence of leaf anatomical traits on photosynthetic in coffee leaves in Yunnan of China

Leaf photosynthesis is largely determined by anatomical features. This study aimed to reveal the quantitative effects of the anatomical structure of Coffea arabica leaves on photosynthesis. Pearsons correlation and path analysis were used to explore the correlation between leaf structure and photosynthesis. To calculate the comprehensive evaluation value of the correlation between leaf anatomical traits and photosynthetic parameters, the Criteria Importance Through Intercriteria Correlation (CRITIC) method was used to obtain the objective weight of each photosynthetic parameter. Most of the anatomical traits of the leaf significantly (P<0.05) to highly significantly (P<0.01) correlated with photosynthetic parameters, suggesting that anatomical traits greatly affected the photosynthetic capacity in Coffea arabica leaf. Likewise, path coefficient analysis revealed that the photosynthetic capacity of Arabic coffee leaves is strongly correlated, both directly and indirectly, with the stomatal characteristics of the leaves. The results of the comprehensive evaluation also indicated that leaf thickness (LT) and stomatal density (d) were the anatomical characteristics most closely related to photosynthesis. In these results, understanding the effects of the anatomical structure of coffee leaves on photosynthesis, may provide useful information for coffee breeding programs and the management of coffee plantations to increase photosynthesis.

biophysics↗

bioRxiv2021

Metabolic profiling of serum for osteoarthritis biomarkers

Osteoarthritis is a prevalent aging disease in the world, and in recent years it has shown a trend toward younger age, which is becoming a major health problem in the world and seriously endangers the health of the elderly. However, the etiology and pathogenesis of osteoarthritis are still unclear, causing great trouble for treatment. To screen out potential biomarkers that could be used as identification of osteoarthritis and explore the pathogenesis of osteoarthritis, we performed untargeted metabolomics analysis of nine New Zealand rabbit serum samples by LC-MS / MS, including three normal serum samples (control group) and six osteoarthritis serum samples (case group). Finally 44 differential metabolites were identified, and the ROC analysis results indicated that a total of 36 differential metabolites could be used as potential biomarkers. Further metabolic pathway enrichment analysis was performed on these differential metabolites, and we found that a total of 17 metabolic pathways were affected, which may provide directions for the study of osteoarthritis mechanisms.

bioinformatics↗

bioRxiv2021

Diversity analysis of soil microbial population abundance before and after planting JunCao "Oasis No.1" in saline-alkali soil

In order to explore the difference of soil microbial population structure and abundance before and after planting JunCao "Oasis No. 1" in saline-alkali soil, verify the improvement effect of JunCao "Oasis No. 1" on microbial population structure and abundance in saline-alkali soil. Samples were collected from the blank saline area with and without JunCao "Oasis NO.1" and no plant growth on the surface, respectively, as Experimental group soil samples (S.Y.1-S.Y.8) and Blank group soil samples (K.B.1-K.B.8).16sDNA high-throughput sequencing technology was used for sequencing analysis respectively, and the diversity of microbial population abundance between them was compared and analyzed.The results showed that the diversity of microbial population abundance in the experimental group was significantly higher than that in the blank group, and the diversity of microbial population abundance in the experimental group was significantly different from that in the blank group, indicating that the composition of microbial population in the experimental group was significantly different from that in the blank group. In the OTU cluster analysis, the number of OTU clusters in the Experimental group soil samples (S.Y.1-S.Y.8) was significantly higher than that in the Blank group soil samples (K.B.1-K.B.8). In the sample complexity analysis of -diversity analysis, the richness and diversity of microbial population in soil samples of Experimental group (S.Y.1-S.Y.8) were significantly higher than that in soil samples of Blank group (K.B.1-K.B.8), which was clearly reflected in the Species accumulation boxplot and Graph of species diversity. In the {beta}-diversity analysis, PcoA, PCA and NMDS analysis methods were used to analyze the difference of microbial population diversity between Experimental soil samples (S.Y.1-S.Y.8) and Blank soil samples (K.B.1-K.B.8). The results showed that the diversity of microbial population in Experimental soil sample (S.Y.1-S.Y.8) was significantly different from that in Blank soil sample (K.B.1-K.B.8). In this paper, 16sDNA high-throughput sequencing technology was used to analyze the diversity of microbial population abundance between Blank soil samples and Experimental soil samples, and it was proved that JunCao "Oasis No. 1" had good saline-alkali soil improvement characteristics. It can effectively increase the abundance of microbial population in saline-alkali soil, so as to restore the microbial population ecosystem in saline-alkali soil, which has important application value in soil saline-alkali control.

microbiology↗

bioRxiv2021

Characterization of pyridomycin B reveals the formation of functional groups in antimycobacterial pyridomycin

Pyridomycin, a cyclodepsipeptide with potent antimycobacterial activity, specifically inhibits the InhA enoyl reductase of Mycobacteria tuberculosis. Structure-activity relationship studies indicated that the enolic acid moiety in pyridomycin core system is an important pharmacophoric group and the natural configuration of the C-10 hydroxyl contributes to the bioactivity of pyridomycin. The ring structure of pyridomycin was generated by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) hybrid system (PyrE-F-G). Bioinformatics analysis reveals that SDR family protein Pyr2 functions as a 3-oxoacyl ACP reductase in the pyridomycin pathway. Inactivation of pyr2 resulted in accumulation of pyridomycin B, a new pyridomycin analogue featured with enol moiety in pyridyl alanine moiety and a saturated 3-methylvaleric acid group. The elucidated structure of pyridomycin B suggests that rather than functioning as a post-tailoring enzyme, Pyr2 catalyzes ketoreduction to form the C-10 hydroxyl group in pyridyl alanine moiety and the double bond formation of the enolic acid moiety derived from isoleucine when the intermediate assembled by PKS-NRPS machinery is still tethered to the last NRPS module, in a special energy-saving manner. Ser-His-Lys residues constitute the active site of Pyr2, which is different from the typically conserved Tyr based catalytic triad in the majority of SDRs. Site-directed mutation identified that His154 in the active site is a critical residue for pyridomycin B production. These findings will improve our understanding of the pyridomycin biosynthetic logic, identify the missing link for the double bound formation of enol ester in pyridomycin and enable creating chemical diversity of pyridomycin derivatives. ImportanceTuberculosis (TB) is one of the worlds leading causes of death by infection. Recently, pyridomycin, the antituberculous natural product from Streptomyces has garnered considerable attention for being determined as a target inhibitor of InhA enoyl reductase of Mycobacteria tuberculosis. In this study, we report a new pyridomycin analogue from mutant HTT12, demonstrate the essential role of a previously ignored gene pyr2 in pyridomycin biosynthetic pathway, and imply that Pyr2 functions as a trans ketoreductase (KR) contributing to the formation of functional groups of pyridomycin utilize a distinct catalytic mechanism. As enol moiety are important for pharmaceutical activities of pyridomycin, our work would expand the understanding the mechanism of SDR family proteins and set the stage for future bioengineering of new pyridomycin derivatives.

microbiology↗

bioRxiv2021

Elevated transcriptional pausing of RNA polymerase II underlies acquired resistance to radiotherapy

As the mainstay modality for many malignancies, particularly inoperable solid tumors such as nasopharyngeal carcinoma (NPC), ionizing radiation (IR) induces a variety of lesions in genomic DNA, evoking a multipronged DNA damage response to interrupt many cellular processes including transcription. The turbulence in transcription, depending on the nature of DNA lesions, encompasses local blockage of RNA polymerase II (RNAPII) near the damage sites, as well as a less understood genome-wide alteration. How the transcriptional change influences the effectiveness of radiotherapy remains unclear. Using a panel of NPC and lung cancer cell lines, we observe increased phosphorylation at serine 5 (pS5) of the RNAPII after IR, indicating an accumulation of paused RNAPII. Remarkably, a similar increase of pS5 is seen in IR-resistant cells. ChIP-seq analysis of RNAPII distribution confirms this increased pausing both in IR-treated and IR-resistant NPC cells, notably on genes involved in radiation response and cell cycle. Accordingly, many of these genes show downregulated transcripts abundance in IR-resistant cells, and individual knockdown some of them such as TP53 and NEK7 endows NPC cells with varying degrees of IR-resistance. Decreasing pS5 of RNAPII and hence tuning down transcriptional pausing by inhibiting CDK7 reverses IR-resistance both in cell culture and xenograft models. Our results therefore uncover an unexpected link between elevated transcriptional pausing and IR-resistance. Given the recurrent NPC tissues display a steady increase in pS5 compared to the paired primary tissues, we suggest that CDK7 inhibitors can be used in combination with radiotherapy to increase sensitivity and thwart resistance.

cancer biology↗