Biology subjects

Wang, Q.

Publications and source records attributed to Wang, Q..

At least 559 records · Page 31Linked to original sources

bioRxiv2022

Differential Requirement of DICER1 Activity during Development of Mitral and Tricuspid Valves

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivated Dicer1 in the endocardium during cardiogenesis, and unexpectedly found that Dicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically. Summary statementAlthough mitral and tricuspid heart valves are both derived from same cell sources in the atrioventricular region through similar initiation and remodeling processes, congenital dysplasia simultaneously affecting both valves is clinically uncommon. We show that DICER1 activity is only essential for mitral valve development whereas it is dispensable for other valves. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that is differentially required to regulate mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.

developmental biology↗

bioRxiv2022

Cancer-driving mutations are enriched in genic regions intolerant to germline variation

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic sub-regions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. Here, we hypothesized that mitotically mutable genic sub-regions that are intolerant to germline variation are enriched for cancer-driving mutations. We introduce a new metric, OncMTR, which uses 125,748 exomes in the gnomAD database to identify genic sub-regions intolerant to germline variation but enriched for hematologic somatic variants. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Finally, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR dramatically improves genetic signals for hematologic malignancies. Our web app enables easy visualization of OncMTR scores for each protein-coding gene (https://astrazeneca-cgr-publications.github.io/OncMTR-Viewer/).

genomics↗

bioRxiv2022

Genomic perspectives on the emerging SARS-CoV-2 Omicron variant

A new variant of concern for SARS-CoV-2, Omicron (B.1.1.529), was designated by the World Health Organization on November 26, 2021. This study analyzed the viral genome sequencing data of 108 samples collected from patients infected with Omicron. First, we found that the enrichment efficiency of viral nucleic acids was reduced due to mutations in the region where the primers anneal to. Second, the Omicron variant possesses an excessive number of mutations compared to other variants circulating at the same time (62 vs. 45), especially in the Spike gene. Mutations in the Spike gene confer alterations in 32 amino acid residues, which was more than those observed in other SARS-CoV-2 variants. Moreover, a large number of nonsynonymous mutations occur in the codons for the amino acid residues located on the surface of the Spike protein, which could potentially affect the replication, infectivity, and antigenicity of SARS-CoV-2. Third, there are 53 mutations between the Omicron variant and its closest sequences available in public databases. Many of those mutations were rarely observed in the public database and had a low mutation rate. In addition, the linkage disequilibrium between these mutations were low, with a limited number of mutations (6) concurrently observed in the same genome, suggesting that the Omicron variant would be in a different evolutionary branch from the currently prevalent variants. To improve our ability to detect and track the source of new variants rapidly, it is imperative to further strengthen genomic surveillance and data sharing globally in a timely manner.

genomics↗

bioRxiv2022

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 [A]. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

biophysics↗

bioRxiv2021

Functional properties of the spike glycoprotein of the emerging SARS-CoV-2 variant B.1.1.529

The recently emerged B.1.1.529 (Omicron) SARS-CoV-2 variant has a highly divergent spike (S) glycoprotein. We compared the functional properties of B.1.1.529 S with those of previous globally prevalent SARS-CoV-2 variants, D614G and B.1.617.2. Relative to these variants, B.1.1.529 S exhibits decreased processing, resulting in less efficient syncytium formation and lower S incorporation into virus particles. Nonetheless, B.1.1.529 S supports virus infection equivalently. B.1.1.529 and B.1.617.2 S glycoproteins bind ACE2 with higher affinity than D614G S. The unliganded B.1.1.529 S trimer is less stable at low temperatures than the other SARS-CoV-2 spikes, a property related to spike conformation. Upon ACE2 binding, the B.1.1.529 S trimer sheds S1 at 37 degrees but not at 0 degrees C. B.1.1.529 pseudoviruses are relatively resistant to neutralization by sera from convalescent COVID-19 patients and vaccinees. These properties of the B.1.1.529 spike glycoprotein likely influence the transmission, cytopathic effects and immune evasion of this emerging variant.

microbiology↗

bioRxiv2021

High-fidelity Cas13 variants for targeted RNA degradation with minimal collateral effect

CRISPR-Cas13 systems have recently been employed for targeted RNA degradation in various organisms. However, collateral degradation of bystander RNAs has imposed a major barrier for their in vivo applications. We designed a dual-fluorescent reporter system for detecting collateral effects and screening Cas13 variants in mammalian cells. Among over 200 engineered variants, several Cas13 variants (including Cas13d and Cas13X) exhibit efficient on-target activity but markedly reduced collateral activity. Furthermore, transcriptome-wide off-targets and cell growth arrest induced by Cas13 are absent for these variants. Importantly, high-fidelity Cas13 variants show comparable RNA knockdown activity with wild-type Cas13 but no detectable collateral damage in transgenic mice and adeno-associated virus-mediated somatic cell targeting. Thus, high-fidelity Cas13 variants with minimal collateral effect are now available for targeted degradation of RNAs in basic research and therapeutic applications.

molecular biology↗

bioRxiv2021

Adjustment for SNPs instead of demographic and clinical covariates in GWAS

With capabilities of sequencing ancient DNA to high coverage often limited by sample quality or cost, imputation of missing genotypes presents a possibility to increase power of inference as well as cost-effectiveness for the analysis of ancient data. However, the high degree of uncertainty often associated with ancient DNA poses several methodological challenges, and performance of imputation methods in this context has not been fully explored. To gain further insights, we performed a systematic evaluation of imputation of ancient data using Beagle 4.0 and reference data from phase 3 of the 1000 Genomes project, investigating the effects of coverage, phased reference and study sample size. Making use of five ancient samples with high-coverage data available, we evaluated imputed data with respect to accuracy, reference bias and genetic affinities as captured by PCA. We obtained genotype concordance levels of over 99% for data with 1x coverage, and similar levels of accuracy and reference bias at levels as low as 0.75x. Our findings suggest that using imputed data can be a realistic option for various population genetic analyses even for data in coverage ranges below 1x. We also show that a large and varied phased reference set as well as the inclusion of low-to moderate-coverage ancient samples can increase imputation performance, particularly for rare alleles. In-depth analysis of imputed data with respect to genetic variants and allele frequencies gave further insight into the nature of errors arising during imputation, and can provide practical guidelines for post-processing and validation prior to downstream analysis.

genetics↗

bioRxiv2021

MIG-23 is involved in sperm migration in Ascaris suum

In nematodes, spermiogenesis, which is also called sperm activation, is a process in which nonmotile spermatids are transformed into crawling spermatozoa, which is accompanied by a series of morphological, physiological and biochemical changes. Sperm motility acquisition during this process is essential for successful fertilization. However, the mechanisms of sperm motility regulation in nematodes remain to be clarified. Herein, we found that extracellular adenosine-5-triphosphate (ATP) level mediation by MIG-23, which is a homolog of human ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), was required for major sperm protein (MSP) filament dynamics and sperm motility in the nematode Ascaris suum. MIG-23 was localized on the sperm plasma membrane. During sperm activation, mitochondrial activity was increased dramatically, and a large amount of ATP was produced and stored in refringent granules (RGs). In addition, a portion of the produced ATP was released to the extracellular space through ATP channels, which were composed of innexins and localized on the sperm plasma membrane. Spermatozoa, instead of spermatids, hydrolyzed exogenous ATP and processed ecto-ATPase activity. MIG-23 contributed to the ecto-ATPase activity of spermatozoa. Once MIG-23 activity was interrupted, spermatozoa also decreased their ATP hydrolysis activity. Blocking MIG-23 activity resulted in an increase in the depolymerization rate of MSP filaments in pseudopodia, which eventually affected nematode sperm migration. Overall, our data imply that MIG-23, which contributes to the ecto-ATPase activity of spermatozoa, regulates sperm migration by modulating extracellular ATP levels. HighlightsO_LIATP is released to extracellular space through innexin channels which are identified in worm sperm. C_LIO_LIWorm spematozoa show ecto-ATPase activity. C_LIO_LIMIG-23 contributes to the ecto-ATPase activity of spermatozoa and regulates extracellular ATP level. C_LIO_LIMIG-23 is required for MSP-based filament dynamics and sperm migration. C_LI

cell biology↗

bioRxiv2021

Two Stages of Speech Envelope Tracking in Human Auditory Cortex Modulated by Speech Intelligibility

The envelope is essential for speech perception. Recent studies have shown that cortical activity can track the acoustic envelope. However, whether the tracking strength reflects the extent of speech intelligibility processing remains controversial. Here, using stereo-electroencephalogram (sEEG) technology, we directly recorded the activity in human auditory cortex while subjects listened to either natural or noise-vocoded speech. These two stimuli have approximately identical envelopes, but the noise-vocoded speech does not have speech intelligibility. We found two stages of envelope tracking in auditory cortex: an early high-{gamma} (60-140 Hz) power stage (delay {approx} 49 ms) that preferred the noise-vocoded speech, and a late {theta} (4-8 Hz) phase stage (delay {approx} 178 ms) that preferred the natural speech. Furthermore, the decoding performance of high-{gamma} power was better in primary auditory cortex than in non-primary auditory cortex, consistent with its short tracking delay. We also found distinct lateralization effects: high-{gamma} power envelope tracking dominated left auditory cortex, while {theta} phase showed better decoding performance in right auditory cortex. In sum, we suggested a functional dissociation between high-{gamma} power and {theta} phase: the former reflects fast and automatic processing of brief acoustic features, while the latter correlates to slow build-up processing facilitated by speech intelligibility.

neuroscience↗

bioRxiv2021

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

cancer biology↗

bioRxiv2021

Develop an efficient and specific AAV-based labeling system for Muller glia in mice

Cell degeneration in the retina leads to several ocular diseases and vision loss. Considerable research efforts focus on reprogramming Muller glia (MG) into functional cells to rescue vision as a promising therapeutic strategy, although whether MG can convert into functional bipolar cells, retinal ganglia cells (RGCs), rods or cones in mammals remains controversial. The broad applicability of tracking MG differentiation thus presents a need for improved labeling efficiency and specificity. Here, we compared AAV-based labeling strategies with conventional lineage-tracking by crossing transgenic mouse lines. We found that reporter expression was weak and not MG-specific in mGFAP-Cre transgenic mice. Different AAV serotypes showed a range of efficiency and specificity in labeling MG, leading us to optimize a human GFAP-Cre reporter system packaged in the AAV9 serotype with the WPRE (WPRE, woodchuck hepatitis virus post-transcriptional regulatory element) removed. The hGFAP-Cre- {Delta}WPRE reporter could label 20-73.8% MGs, with non-specific RGC labeling rates ranging from 0-0.08% at doses of 1 x 108 to 1010 vector genomes (vg) per eye, an approximate 40-fold reduction compared with the AAV9-hGFAP-Cre-WPRE labeling system. Furthermore, we validated the availability of the label system to trace MG reprogramming and also detected false-positive results reported previously. The AAV9-hGFAP-Cre-{Delta}WPRE system thus represents a highly efficient and specific labeling system for MG, providing a valuable tool for tracking cell fate in vivo.

neuroscience↗

bioRxiv2021

Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its pathological conformational conversion

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by the selective death of motor neurons. Misfolded Cu, Zn-superoxide dismutase (SOD1) has been linked to both familial ALS and sporadic ALS. SOD1 fibrils formed in vitro are able to incorporate into cells, transmit intercellularly, and share toxic properties with ALS inclusions. Here we produced amyloid fibrils in vitro from recombinant, full-length apo human SOD1 under semi-reducing conditions and determined the atomic structure using cryo-EM. The SOD1 fibril consists of a single protofibril with a left-handed helix. The fibril core exhibits a serpentine fold comprising N-terminal segment (residues 3 to 55) and C-terminal segment (residues 86 to 153) with a structural break. The two segments are zipped up by three salt bridge pairs. By comparison with the structure of apo SOD1 dimer, we propose that eight {beta}-strands (to form a {beta}-barrel) and one -helix in the subunit of apo SOD1 convert into thirteen {beta}-strands stabilized by five hydrophobic cavities in the SOD1 fibril. Our data provide insights into how SOD1 converts between structurally and functionally distinct states.

biochemistry↗

bioRxiv2021

Consequence of adjustments for demographic or clinical covariates and a recommended solution in genome-wide association studies

Genome-wide association study (GWAS) is fundamentally designed to detect disease-causing genes. To reduce spurious associations or improve statistical power, about 80% of GWASs arbitrarily adjusted for demographic or clinical covariates. However, adjustment strategies in GWASs have not achieved consistent conclusions. Given the initial aim of GWAS that is to identify the causal association between a specific causal single-nucleotide polymorphism (SNP) and disease trait, we summarized all complex relationships of the target SNP, covariate and disease trait into 15 causal diagrams according to various roles of the covariate. Following each causal diagram, we conducted a series of theoretical justifications and statistical simulations. Our results demonstrate that it is unadvisable to adjust for any demographic or clinical covariates. We illustrate our point by applying GWASs for body mass index (BMI) and breast cancer, including adjusting and non-adjusting for age and smoking status. Genetic effects and P values might vary across different strategies. Instead, adjustments for SNPs (G') should be strongly recommended when G' are in linkage disequilibrium with the target SNP, and correlated with disease trait conditional on the target SNP. Specifically, adjustment for such G' can block all the confounding paths between the target SNP and disease trait, and avoid over-adjusting for colliders or intermediaries.

bioinformatics↗

bioRxiv2021

Inference of Brain States under Anesthesia with Meta Learning Based Deep Learning Models

Monitoring the depth of unconsciousness during anesthesia is useful in both clinical settings and neuroscience investigations to understand brain mechanisms. Electroencephalogram (EEG) has been used as an objective means of characterizing brain altered arousal and/or cognition states induced by anesthetics in real-time. Different general anesthetics affect cerebral electrical activities in different ways. However, the performance of conventional machine learning models on EEG data is unsatisfactory due to the low Signal to Noise Ratio (SNR) in the EEG signals, especially in the office-based anesthesia EEG setting. Deep learning models have been used widely in the field of Brain Computer Interface (BCI) to perform classification and pattern recognition tasks due to their capability of good generalization and handling noises. Compared to other BCI applications, where deep learning has demonstrated encouraging results, the deep learning approach for classifying different brain consciousness states under anesthesia has been much less investigated. In this paper, we propose a new framework based on meta-learning using deep neural networks, named Anes-MetaNet, to classify brain states under anesthetics. The Anes-MetaNet is composed of Convolutional Neural Networks (CNN) to extract power spectrum features, and a time consequence model based on Long Short-Term Memory (LSTM) Networks to capture the temporal dependencies, and a meta-learning framework to handle large cross-subject variability. We used a multi-stage training paradigm to improve the performance, which is justified by visualizing the high-level feature mapping. Experiments on the office-based anesthesia EEG dataset demonstrate the effectiveness of our proposed Anes-MetaNet by comparison of existing methods.

bioengineering↗

bioRxiv2021

miR-199-3p Suppresses Cellular Migration and Viability and Promotes Progesterone Production in Goose Ovarian Follicles Before Selection by Targeting ITGB8 and Regulating Other ECM-related Genes

The extracellular matrix (ECM) constitutes the follicular basal lamina and is also present between follicular cells. Remodeling of the ECM is believed to be a key event in follicular development, especially follicular selection, and plays important roles in cell migration, survival, and steroidogenesis. miR-199-3p is differentially expressed in the goose follicular granulosa layer during follicular selection and is reported to play a primary role in inhibiting cell migration and invasion. Nevertheless, the effect of miR-199-3p on ovarian follicles and its role in follicular cellular migration are not understood. In this study, we demonstrated by qRT-PCR that miR-199-3p was differentially expressed in the granulosa layer from goose ovarian follicles before and after follicular selection. Additionally, we found that miR-199-3p overexpression could significantly suppress cell viability and migration, as well as elevate both the concentration of progesterone and the expression of key progesterone production genes in cultured granulosa cells (GCs) from goose pre-hierarchical follicles. Furthermore, using dual-fluorescence reporter experiments on 293T cells, we confirmed that miR-199-3p downregulated the expression of the ECM gene ITGB8 by directly targeting its mRNA three prime untranslated region (3' UTR). Finally, we found that miR-199-3p overexpression in the GCs of goose pre-hierarchical follicles inhibited the expression of two ECM-related genes (MMP9 and MMP15) yet promoted the expression of another two ECM-related genes (COL4A1 and LAMA1). Taken together, these findings suggest that miR-199-3p participates in granulosa cell migration, viability, and steroidogenesis in goose ovarian follicles before selection by targeting ITGB8 and modulating other ECM-related genes. These data highlight the key roles of miR-199-3p in follicular cell migration, viability, and steroidogenesis by regulating ECM-related genes and thus contribute to a better understanding of the mechanisms underlying follicle selection in birds.

molecular biology↗

bioRxiv2021

Cell free extrachromosomal circular DNA is common in human urine

Cell free extrachromosomal circular DNA (eccDNA) is evolving as a potential biomarker in liquid biopsies for disease diagnosis. In this study, an optimized next generation sequencing-based Circle-Seq method was developed to investigate urinary cell free eccDNA (ucf-eccDNA) from 28 adult healthy volunteers (mean age = 28, 19 males/ 9 females). The genomic distributions and sequence compositions of ucf-eccDNAs were comprehensively characterized. Approximately 1.2 million unique ucf-eccDNAs are identified, covering 14.9% of the human genome. Comprehensive characterization of ucf-eccDNAs show that ucf-eccDNAs contain higher GC content than flanking genomic regions. Most eccDNAs are less than 1000 bp and present four pronounced peaks at 203, 361, 550 and 728 bp, indicating the association between eccDNAs and the numbers of intact nucleosomes. Analysis of genomic distribution of ucf-eccDNAs show that eccDNAs are found in all chromosomes but enriched in chromosomes i.e. chr.17, 19 and 20 with high density of protein-codding genes, CpG islands, SINE and simple repeat elements. Lastly, analysis of sequence motif signatures at eccDNA junction sites reveal that direct repeats (DRs) are commonly found, indicating a potential role of DRs in eccDNA biogenesis. This work underscores the deep sequencing analysis of ucf-eccDNAs and provides a valuable reference resource for exploring potential applications of ucf-eccDNA as diagnostic biomarkers of urogenital disorders in the future. Significance StatementExtrachromosomal circular DNA (eccDNA) is an important genetic element and a biomarker for disease diagnosis and treatment. In this study, we conduct a comprehensive characterization of urinary cell free eccDNA (ucf-eccDNA) in 28 heathy subjects. Over one million ucf-eccDNAs are identified. Ucf-eccDNAs are characterized as high GC content. The size of most ucf-eccDNAs is less than 1000 bp and enriched in four peaks resembling the size of single, double, triple, and quadruple nucleosomes. The genomic distribution of ucf-eccDNAs is enriched in generic regions, protein-coding genes, Alu, CpG islands, SINE and simple repeats. Sequence motif analysis of ucf-eccDNA junctions identified simple direct repeats (DRs) commonly presented in most eccDNAs, suggesting potential roles of DRs in eccDNA biogenesis.

genomics↗

bioRxiv2021

Universality and non-universality of the growth law

An approximately linear relationship between the fraction of ribosomal proteins in the proteome ({phi}R) and the growth rate () holds in proliferating cells when the nutrient quality changes, often referred to as a growth law. While a simple model assuming a constant translation speed of ribosomes without protein degradation can rationalize this growth law, real protein synthesis processes are more complex. This work proposes a general theoretical framework of protein synthesis, taking account of heterogeneous translation speeds among proteins and finite protein degradation. We introduce ribosome allocations as the fraction of active ribosomes producing certain proteins, with two correlation coefficients respectively quantifying the correlation between translation speeds and ribosome allocations, and between protein degradation rates and mass fractions. We prove that the growth law curve generally follows{phi} R = ( + c1)/(c2 + c3) where c1, c2, and c3 are constants depending on the above correlation coefficients and the translation speed of ribosomal proteins. Our theoretical predictions of{phi} R agree with existing data of Saccharomyces cerevisiae. We demonstrate that when different environments share similar correlation coefficients, the growth law curve is universal and up-bent relative to a linear line in slow-growth conditions, which appears valid for Escherichia coli. However, the growth law curve is non-universal and environmental-specific when the environments have significantly different correlation coefficients. Our theories allow us to estimate the translation speeds of ribosomal and non-ribosomal proteins based on the experimental growth law curves.

systems biology↗

bioRxiv2021

Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-β selection pre-T cells

Production of a diverse peripheral T cell compartment requires massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment at the DN2 stage and following successful rearrangement and selection for functional TCR{beta} chains in DN3 thymocytes, which promotes development of DN4 cells to the DP stage. Signals driving expansion of DN2 thymocytes are well studied, however, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-{beta}-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor controlling the survival of proliferating post-{beta}-selection thymocytes and demonstrates a key role for the cGAS/STING pathway driving apoptosis of developing T cells.

immunology↗