Biology subjects

Ji, Y.

Publications and source records attributed to Ji, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Efficient 3D cone trajectory design for improved combined angiographic and perfusion imaging using arterial spin labeling

PurposeTo improve the spatial resolution and repeatability of a non-contrast MRI technique for simultaneous time resolved 3D angiography and perfusion imaging by developing an efficient 3D cone trajectory design. MethodsA novel parameterized 3D cone trajectory design incorporating the 3D Golden Angle was integrated into 4D combined angiography and perfusion using radial imaging and arterial spin labeling (CAPRIA) to achieve higher spatial resolution and sampling efficiency for both dynamic angiography and perfusion imaging with flexible spatiotemporal resolution. Numerical simulations and physical phantom scanning were used to optimize the cone design. Eight healthy volunteers were scanned to compare the original radial trajectory in 4D CAPRIA with our newly designed cone trajectory. A locally low rank reconstruction method was used to leverage the complementary k-space sampling across time. ResultsThe improved sampling in the periphery of k-space obtained with the optimized 3D cone trajectory resulted in improved spatial resolution compared with the radial trajectory in phantom scans. Improved vessel sharpness and perfusion visualization were also achieved in vivo. Less dephasing was observed in the angiograms due to the short echo time of our cone trajectory and the improved k-space sampling efficiency also resulted in higher repeatability compared to the original radial approach. ConclusionThe proposed 3D cone trajectory combined with 3D Golden Angle ordering resulted in improved spatial resolution and image quality for both angiography and perfusion imaging and could potentially benefit other applications that require an efficient sampling scheme with flexible spatial and temporal resolution.

neuroscience↗

bioRxiv2023

Optimal distance metrics for single-cell RNA-seq populations

In single-cell data workflows and modeling, distance metrics are commonly used in loss functions, model evaluation, and subpopulation analysis. However, these metrics behave differently depending on the source of variation, conditions and subpopulations in single-cell expression profiles due to data sparsity and high dimensionality. Thus, the metrics used for downstream tasks in this domain should be carefully selected. We establish a set of benchmarks with three evaluation measures, capturing desirable facets of absolute and relative distance behavior. Based on seven datasets using perturbation as ground truth, we evaluated 16 distance metrics applied to scRNA-seq data and demonstrated their application to three use cases. We find that linear metrics such as mean squared error (MSE) performed best across our three evaluation criteria. Therefore, we recommend the use of MSE for comparing single-cell RNA-seq populations and evaluating gene expression prediction models.

bioinformatics↗

bioRxiv2023

Phylogeny-metabolism dual-directed single-cell genomics for dissecting and mining ecosystem function

Although microbiome-wide association studies (MWAS) have uncovered many marker organisms for an ecosystem trait, mechanisms of most microbiota-mediated processes remain elusive, due to challenges in validating the markers in situ metabolic activities and tracing such activities to individual genomes. Here we introduced a phylogeny-metabolism dual-directed single-cell genomics approach called Fluorescence-In-Situ-Hybridization-guided Single-Cell Raman-activated Sorting and Sequencing (FISH-scRACS-Seq). It directly localizes individual cells from target taxon via a FISH probe for marker organism, profiles their in situ metabolic functions via single-cell Raman spectra, sorts cells of target taxonomy and target metabolism, and produces indexed, high-coverage and precisely-one-cell genomes. From cyclohexane-contaminated seawater, cells representing the MWAS-derived marker taxon of {gamma}-Proteobacteria and that are actively degrading cyclohexane in situ were directly identified via FISH and Raman respectively, then sorted and sequenced for one-cell full genomes. In such a Pseudoalteromonas fuliginea cell, we discovered a three-component cytochrome P450 system that can convert cyclohexane to cyclohexanol in vitro, representing a previously unknown group of cyclohexane-degrading enzymes and organisms. By culture-independently unveiling enzymes, pathways, genomes and their in situ functions specifically for those single-cells with ecological relevance, FISH-scRACS-Seq is a rational and generally applicable approach for dissecting and mining microbiota functions. TeaserFISH-scRACS-Seq is a new strategy to dissect microbiota functional mechanism at single-cell resolution.

microbiology↗

bioRxiv2023

3-phenyllactic acid promotes healthspan through SKN-1/ATFS-1-mediated mitochondrial activation and stress resilience

The mechanisms underlying the impact of probiotic supplementation on health remain largely elusive. While previous studies have primarily focused on the discovery of novel bioactive bacteria and alterations in the microbiome environment to explain potential probiotic effects, our research delves into the role of living lactic acid bacteria (LAB) and their conditioned media, highlighting that only the former, not dead bacteria, enhance the healthspan of Caenorhabditis elegans. To elucidate the underlying mechanisms, we conducted transcriptomic profiling through RNA-seq analysis in C. elegans exposed to LAB or 3-phenyllactic acid (PLA), mimicking the presence of key candidate metabolites of LAB and evaluating healthspan. Our findings reveal that PLA treatment significantly extends the healthspan of C. elegans by promoting energy metabolism and stress resilience in a SKN-1/ATFS-1-dependent manner. Moreover, PLA-mediated longevity is associated with a novel age-related parameter, the Healthy Aging Index (HAI), introduced in this study, which comprises healthspan-related factors such as motility, oxygen consumption rate (OCR), and ATP levels. Extending the relevance of our work to humans, we observed an inverse correlation between blood PLA levels and physical performance in patients with sarcopenia, when compared to age-matched non-sarcopenic controls. Our investigation thus sheds light on the pivotal role of the metabolite PLA in probiotics-mediated enhancement of organismal healthspan, and also hints at its potential involvement in age-related sarcopenia. These findings warrant further investigation to delineate PLAs role in mitigating age-related declines in healthspan and resilience to external stressors. HighlightsO_LIMetabolites Produced by Lactic Acid Bacteria Function as Mediators of Longevity in C. elegans C_LIO_LI3-Phenyllactic Acid (PLA) Augmented Lifespan Extension and Elevated the Healthy Aging Index (HAI) C_LIO_LIPLA Facilitated Healthy Aging by Inducing Mitochondrial Activation and Stress Resistance Dependent on SKN-1/ATFS-1 C_LIO_LIPatients with Sarcopenia and Symptoms of Frailty Exhibited Reduced Blood PLA Levels. C_LI

molecular biology↗

bioRxiv2023

Cellular COPI components promote geminivirus infections by facilitating the chloroplast localization of viral C4/AC4 proteins

Geminiviruses are a family of viruses that infect numerous crops and cause extensive agricultural losses worldwide. During viral infection, geminiviral C4/AC4 proteins relocate from the plasma membrane (PM) to chloroplasts, where they inhibit chloroplast-mediated host defense, including the biosynthesis of salicylic acid (SA). However, how are C4/AC4 proteins transported to chloroplasts is unknown. We report here that the Coat Protein I (COPI) components play a critical role in redistributing Tomato yellow leaf curl virus (TYLCV) C4 protein to chloroplasts. TYLCV C4 interacts with the {beta} subunit of COPI, and the coexpression of both in Nicotiana benthamiana cells promotes the enrichment of C4 in chloroplasts, which also occurs during TYLCV infection and is blocked by an inhibitor of the COPI pathway. Overexpression of COPI components promotes but knockdown of gene expression inhibits TYLCV infection. The COPI pathway plays similar roles in C4/AC4 transport and infections of other geminiviruses, including Beet curly top virus and East African cassava mosaic virus. Our results identify an unconventional role of the COPI pathway in protein trafficking to chloroplasts during geminiviruses infections in plants, and suggest a broad-spectrum antiviral strategy in controlling geminiviruses by manipulating COPI components.

plant biology↗

bioRxiv2023

SCF cyclin F - EXO1 axis controls cell cycle dependent execution of double strand break repair

Ubiquitination is a crucial post-translational modification required for the proper repair of DNA double-strand breaks (DSBs) induced by ionising radiation (IR). DSBs are mainly repaired through homologous recombination (HR) when template DNA is present and non-homologous end joining (NHEJ) in its absence. Additionally, microhomology-mediated end joining (MMEJ) and single strand annealing (SSA) provide back-up DSBs repair pathways. However, the mechanisms controlling their use remain poorly understood. By employing a high-resolution CRISPR screen of the ubiquitin system after IR, we systematically uncover genes required for cell survival and elucidate a critical role of the E3 ubiquitin ligase SCFcyclin F in cell cycle-dependent DSB repair. We show that SCFcyclin F -mediated EXO1 degradation prevents DNA end resection in mitosis, allowing MMEJ to take place. Moreover, we identify a conserved cyclin F recognition motif, distinct from the one used by other cyclins, with broad implications in cyclin specificity for cell cycle control.

cell biology↗

bioRxiv2023

GRAMD2+ alveolar type I cell plasticity facilitates cell state transitions in organoid culture

Alveolar epithelial regeneration is critical for normal lung function and becomes dysregulated in disease. While alveolar type 2 (AT2) and club cells are known distal lung epithelial progenitors, determining if alveolar epithelial type 1 (AT1) cells also contribute to alveolar regeneration has been hampered by lack of highly specific mouse models labeling AT1 cells. To address this, the Gramd2CreERT2 transgenic strain was generated and crossed to RosamTmG mice. Extensive cellular characterization, including distal lung immunofluorescence and cytospin staining, confirmed that GRAMD2+ AT1 cells are highly enriched for green fluorescent protein (GFP). Interestingly, Gramd2CreERT2 GFP+ cells were able to form organoids in organoid co-culture with Mlg fibroblasts. Temporal scRNAseq revealed that Gramd2+ AT1 cells transition through numerous intermediate lung epithelial cell states including basal, secretory and AT2 cell in organoids while acquiring proliferative capacity. Our results indicate that Gramd2+ AT1 cells are highly plastic suggesting they may contribute to alveolar regeneration.

cell biology↗

bioRxiv2023

RAG1 and RAG2 non-core regions are implicated in the leukemogenesis and off-target V(D)J recombination in BCR-ABL1-driven B cell lineage lymphoblastic leukemia.

The evolutionary conservation of non-core RAG regions suggests significant roles that might involve quantitative or qualitative alterations in RAG activity. Off-target V(D)J recombination contributes to lymphomagenesis and is exacerbated by RAG2 C-terminus absence in Tp53-/- mice thymic lymphomas. However, the genomic stability effects of non-core regions from both cRAG1 and cRAG2 in BCR-ABL1+ Blymphoblastic leukemia (BCR-ABL1+ B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remains unclear. Here, we established three mouse models of BCR-ABL1+ B-ALL in mice expressing full-length RAG (fRAG), core RAG1 (cRAG1), and core RAG2 (cRAG2). The cRAG (cRAG1 and cRAG2) leukemia cells exhibited greater malignant tumor characteristics compared to fRAG cells. Additionally, cRAG cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than fRAG. We also revealed decreased RAG cleavage accuracy in cRAG cells and a smaller recombinant size in cRAG1 cells, which could potentially exacerbate off-target V(D)J recombination in cRAG cells. In conclusion, these findings indicate that the non-core RAG regions, particularly the non-core region of RAG1, play a significant role in preserving V(D)J recombination precision and genomic stability in BCR-ABL1+ B-ALL.

immunology↗

bioRxiv2023

Elevated serotonin in mouse spinal dorsal horn is pronociceptive

Serotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathological pain states, but whether changes in serotonergic mechanisms are pro or anti-nociceptive are debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naive mice produces mechanical hypersensitivity and conditioned place aversion. Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase is sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain. Significance StatementSerotonergic neurons of the rostral ventral medulla participate in descending pain modulation by regulating spinal and trigeminal nociceptive circuits. Whether changes in serotonergic mechanisms are pro or anti-nociceptive is debated. We show that serotonin release within the spinal trigeminal nucleus is pronociceptive and that enhanced tonic, but not phasic serotonin release may contribute to sensitization in mouse models of chronic pain. These results further clarify the role of serotonin in nociception and suggest that local inhibition of serotonin release or increase of uptake may be a viable therapeutic approach in treating chronic pain.

neuroscience↗

bioRxiv2023

Comprehensive analyses of 1771 transcriptome from seven tissues enhance genetic and biological interpretations of maize complex traits

By analyzing 1771 RNA-seq datasets from seven tissues in a maize diversity panel, we explored the landscape of multi-tissue transcriptome variation and evolution patterns of tissue-specific genes, and built a comprehensive multi-tissue gene regulation atlas to understand the genetic regulation of maize complex trait. Using transcriptome-wide association analysis, we linked tissue-specific expression variation of 45 genes to variation of 11 agronomic traits. Through integrative analyses of tissue-specific gene regulatory variation with genome-wide association studies, we detected relevant tissue types and candidate genes for a number of agronomic traits, including leaf during the day for anthesis-silking interval (GRMZM2G093210), leaf during the day for kernel Zeinoxanthin level (GRMZM2G143202), and root for ear height (GRMZM2G700665), highlighting the contribution from tissue-specific gene expression to variation of agronomic trait. Our findings provide novel insights into the genetic and biological mechanisms underlying complex traits in maize, and the multi-tissue regulatory atlas serves as a primary source for biological interpretation, functional validation, and genomic improvement of maize.

genetics↗

bioRxiv2023

Polygenic basis of strong and rapid flowering time response to environment perturbations in wild Arabidopsis thaliana population

Despite the importance in understanding the impact of climate change, the genetics of rapid response to changing environments and its role in adaptive evolution remains elusive. Here, we studied flowering time response to environment changes using 514 Arabidopsis thaliana worldwide accessions with re-sequencing genomes and flowering time measurements from ten unique environments with variable temperature, drought, daylight and competition stresses. We revealed a polygenic basis of flowering time mean and plasticity, underpinned by 52 mean and plasticity QTL. Widespread interaction between mean QTL, polygenic background and surrounding environments considerably altered the amount of additive genetic variance and allelic effects of detected QTL. This caused variability in phenotype plasticity and across environment variation in genetic variance, resulting in rapid flowering time response to environment perturbations. In addition, the plastic alleles showed a higher correlation with the environment factors than that from randomly sampled alleles, suggesting a potential role in climate adaptation. We therefore proposed a polygenic interaction model, whereby large effect QTL and polygenic background simultaneously interacted with the surrounding environment, underlying rapid response to changing environments. Results from our study thus provided deeper insights into the genetics of plasticity, with potential benefit in genomic selection of crops in heterogeneous environments and predicting changes in species distribution and the evolutionary trajectory of wild populations.

genetics↗

bioRxiv2023

Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation

Adipocytes are crucial components of the tumor microenvironment (TME) that play a prominent role in supporting tumor growth. However, the characteristics of cancer-associated adipocytes (CAAs) that contribute to the pro-tumorigenic niche remain to be fully established. Here, we used adipocyte-specific Beclin1 KO (BaKO) mice to investigate the role of maladaptive adipocytes in promoting tumor progression. BECN1-deficient adipocytes exhibited downregulation of adipogenic markers and activation of YAP/TAZ signaling, similar to the traits observed in CAAs. Thus, we generated adipocyte-specific Becn1/Yap1/Taz KO mice, which exhibit markedly restored phenotypes in adipose tissue, resulting in tumor regression compared to that in BaKO. Further, we observed dysregulation of the BECN1-YAP/TAZ axis in the adipose tissue of mice fed a high-fat diet (HFD). Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Our findings provide insights into CAA formation and its significance in determining malignant TME, thereby suggesting a potential dual therapeutic strategy simultaneously targeting adipocyte homeostasis and cancer growth.

biochemistry↗

bioRxiv2023

Spatio-temporal variation of bacterial community structure in two intertidal sediment types of Jiaozhou Bay

The intertidal sediment environment is dynamic and the biofilm bacterial community within it must constantly adjust, but an understanding of the differences in the biofilm bacterial community within sediments of different types is still relatively limited. In this study, the structure of the bacterial community in Jiaozhou Bay sediment biofilms are described using high-throughput 16S rRNA gene sequencing and the effects of temporal change and different sediment environment types are discussed. The Shannon index was significantly higher in sandy samples than in muddy samples. The co-occurrence network was tighter and more species were involved in community building in sandy samples. The principal coordinates analysis identified a significant separation between different sediment types and between stations (LiCun estuary, LC and ZhanQiao Pier, ZQ). Proteobacteria, which had a relative abundance of approximately 50% at all phylum levels, was significantly more abundant at ZQ, while Campilobacterota and Firmicutes were significantly more abundant at LC. The relative abundances of Bacteroidetes, Campilobacterota, Firmicutes, and Chloroflexi were significantly higher in the muddy samples, while Actinobacteria and Proteobacteria were higher in the sandy samples. There were different phylum-level biomarkers between sediment types at different stations. There were also different patterns of functional enrichment in biogeochemical cycles between sediment types and stations with the former having more gene families that differed significantly, highlighting their greater role in determining bacterial function. The RDA results, where each months samples were concentrated individually, showed reduced variation between months when the amplicon sequence variant was replaced by KEGG orthologs, presumably the temporal change had an impact on shaping the intertidal sediment bacterial community, although this was less clear at the gene family level. Random forest prediction yielded a combination of 43 family-level features that responded well to temporal change, reflecting the influence of temporal change on sediment biofilm bacteria. HighlightsO_LISandy sediments have more bacterial species involved in community building. C_LIO_LIDifferent substrates from different stations have their own phylum biomarkers. C_LIO_LISubstrates have a greater influence on shaping bacterial function. C_LIO_LITemporal changes have a greater shaping power on bacteria than on gene families. C_LI Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/542048v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1834e64org.highwire.dtl.DTLVardef@18fc695org.highwire.dtl.DTLVardef@369657org.highwire.dtl.DTLVardef@1c85a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2023

Functional genomics identifies extension of complex N-glycans as a mechanism to evade lysis by natural killer cells

Somatic mutations can lead to the transformation of healthy cells into malignant cells and allow their evasion from immune surveillance. To uncover genes that play a role in the detection and lysis of tumor cells by natural killer (NK) cells, a B lymphoblastoid cell line was subjected to a genome-wide CRISPR screen. Among the top hits that facilitated NK evasion was SPPL3, which encodes an intramembrane protease that cleaves transmembrane glycosyltransferases in the Golgi apparatus. SPPL3-deficient cells accumulated glycosyltransferases, such as acetylglucosaminyltransferase 5 (MGAT5), and displayed increased N-glycosylation. Binding of NK receptors NKG2D and CD2 to their corresponding ligands MICB and CD58, and binding of rituximab to CD20, was disrupted by SPPL3-deletion. Inhibition of N-glycan maturation restored receptor binding and sensitivity to NK cells. To elucidate the mechanism of this resistant phenotype, a secondary CRISPR screen was performed in SPPL3-deficient cells. This screen identified glycosyltransferases that catalyze the formation of highly branched N-glycans and N-acetyl-lactosamine (LacNAc) extensions as key regulators that prevent killing. A significant enrichment of poly-LacNAc-containing tetra-antennary species was confirmed by glycoproteomic analysis. These findings provide mechanistic insight into how SPPL3 deletions have been linked to cancer.

immunology↗

bioRxiv2023

Sex differences in the role of parabrachial in nociception and pain in awake mice

The parabrachial nuclear complex (PBN) is a nexus for aversion, and for the sensory and affective components of pain perception. We have previously shown that, during chronic pain, PBN neurons in anesthetized rodents have amplified activity. We report a method to record from PBN neurons of behaving, head-restrained mice, while applying reproducible noxious stimuli. We find that both spontaneous and evoked activity are higher in awake animals, compared to urethane anesthetized mice. Fiber photometry of calcium responses from CGRP-expressing PBN neurons demonstrates that these neurons respond to nociceptive stimuli. In both males and females with neuropathic or inflammatory pain, responses of PBN neurons remain amplified for at least 5 weeks, in parallel with increased pain metrics. We also show that PBN neurons can be rapidly conditioned to respond to innocuous stimuli, after pairing with nociceptive stimuli. Finally, we demonstrate that changes in PBN neuronal activity are correlated with changes in arousal, measured as changes in pupil diameter. Significance StatementThe parabrachial complex is a nexus of aversion, including pain. We report a method to record from parabrachial nucleus neurons of behaving mice, while applying reproducible noxious stimuli. This allowed, for the first time, tracking the activity of these neurons over time in animals with neuropathic or inflammatory pain. It also allowed us to show that the activity of these neurons correlates with arousal states, and that these neurons can be conditioned to respond to innocuous stimuli.

neuroscience↗

bioRxiv2023

Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells

Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra- proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate JUN/FOS, WNT/{beta}-Catenin, FOXQ1, NF{kappa}B, and JAK/STAT pathways as the major drivers of castration- resistant luminal populations with high relevance to human PCa. Importantly, we demonstrate the utility of our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), to aid in developing novel combination treatments with ARSI for advanced PCa patients. O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/530998v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@8bd384org.highwire.dtl.DTLVardef@1ebc004org.highwire.dtl.DTLVardef@8b4dbforg.highwire.dtl.DTLVardef@19d7052_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Chromosome-level genome assembly of tree sparrow reveals a burst of new genes driven by segmental duplications

The creation of new genes is a major force of evolution. Despite as an important mechanism that generated new genes, segmental duplication (SD) has yet to be accurately identified and fully characterized in birds because the repetitive complexity leads to misassignment and misassembly of sequence. In addition, SD may lead to new gene copies, which makes it possible to test the "out of testis" hypothesis which suggests genes are frequently born with testis-specific expression. Using a high-quality chromosome-level assembly, we performed a systematic analysis and presented a comprehensive landscape of SDs in tree sparrow (Passer montanus). We detected co-localization of newly expanded genes and long terminal repeat retrotransposons (LTR-RTs), both of which are derived from SDs and enriched in microchromosomes. The newly expanded genes are mostly found in eight families including C2H2ZNF, OR, PIM, PAK, MROH, HYDIN, HSF and ITPRIPL. The large majority of new members of these eight families have evolved to pseudogenes, whereas there still some new copies preserved transcriptional activity. Among the transcriptionally active new members, new genes from different families with diverse structures and functions shared a similar testis-biased expression pattern, which is consistent with the "out of testis" hypothesis. Through a case analysis of the high-quality genome assembly of tree sparrow, we reveal that the SDs contribute to the formation of new genes. Our study provides a comprehensive understanding of the emergence, expression and fate of duplicated genes and how the SDs might participate in these processes and shape genome evolution.

genomics↗

bioRxiv2023

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis

Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. Acute myeloid leukemia (AML) is initiated by aberrantly self-renewing malignant stem cells termed leukemia stem cells (LSCs). HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their capacity for self-renewal in the setting of proliferative stress and leukemogenesis remain unknown. Here we show CD99, a cell surface protein upregulated in LSCs, is required for self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, they show that similar to HSCs, LSCs depend on regulated protein synthesis.

cancer biology↗