Biology subjects

Xu, S.

Publications and source records attributed to Xu, S..

At least 217 records · Page 12Linked to original sources

bioRxiv2024

Temporally controlled nervous system-to-gut signaling bidirectionally regulates longevity in Caenorhabditis elegans

The nervous system modulates aging by secreting signaling molecules to cell-nonautonomously regulate the physiological state of distal tissues such as the gut. However, the underlying mechanisms are not well understood. Here, using C. elegans as a model, we identified two distinct neuroendocrine signaling circuits through which motor neurons signal the gut in early life to shorten lifespan but in mid-late life to extend lifespan. Both circuits employ the same neurotransmitter acetylcholine (ACh), while recruiting two different gut ACh receptors ACR-6 and GAR-3 to regulate the transcription factor DAF-16 and HSF-1 in early and mid-late life, respectively. Strikingly, the gut expression of ACR-6 is restricted to early life, whereas that of GAR-3 is confined to mid-late life, providing a potential mechanism for the temporal control of the two circuits. These results identify a novel mechanism that empowers the nervous system to bidirectionally regulate longevity by differentially signaling the gut at different life stages.

cell biology↗

bioRxiv2024

PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity

Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising multiple subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses of thousands of patient tumors, we identified enhanced PGC-1--a potent regulator of oxidative phosphorylation (OXPHOS)--in various SCN cancers (SCNCs), closely linked with neuroendocrine differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing neuroendocrine subtype showed elevated PGC-1 expression and increased OXPHOS activity. Inhibition of PGC-1 and OXPHOS reduced the proliferation of SCN lung and prostate cancer cell lines and blocked SCN prostate tumor formation. Conversely, enhancing PGC- 1 and OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate and promoted commitment to the ASCL1 lineage. These results establish PGC-1 as a driver of SCNC progression and subtype determination, highlighting novel metabolic vulnerabilities in SCNCs across different tissues. STATEMENT OF SIGNIFICANCEOur study provides functional evidence that metabolic reprogramming can directly impact cancer phenotypes and establishes PGC-1-induced mitochondrial metabolism as a driver of SCNC progression and lineage determination. These mechanistic insights reveal common metabolic vulnerabilities across SCNCs originating from multiple tissues, opening new avenues for pan-SCN cancer therapeutic strategies.

cancer biology↗

bioRxiv2024

AncestryPainter 2.0: Visualizing ancestry composition and admixture history graph

To effectively depict the results of population genetics studies, it is essential to present ancestry composition and genetic distance. The growing amount of genomic data prompted us to design AncestryPainter 1.0, a Perl program to display the ancestry composition of numerous individuals using a rounded graph. Motivated by the requests of users in practical applications, we updated AncestryPainter to version 2.0 by coding in an R package and improving the layout, providing more options and compatible statistical functions for graphing. In particular, AncestryPainter 2.0 implements a method admixture history graph (AHG) to infer the admixture sequence of multiple ancestry populations, and allows for multiple pie charts at the center of the graph to display the ancestry composition of more than one target population. We also introduced an additional graphing module to visualize genetic distance through radial bars of varying lengths surrounding a core. Visualization functions per se have been enhanced in this update as well. Furthermore, AncestryPainter 2.0 includes two statistical modules to 1) merge ancestry proportion matrices and 2) infer admixture sequences through correlation analyses. AncestryPainter 2.0 is publicly available at https://github.com/Shuhua-Group/AncestryPainterV2 and https://pog.fudan.edu.cn/#/Software.

genetics↗

bioRxiv2024

PsiPartition: Improved Site Partitioning for Genomic Data by Parameterized Sorting Indices and Bayesian Optimization

Phylogenetics has been widely used in molecular biology to infer the evolutionary relationships among species. With the rapid development of sequencing technology, genomic data with thousands of sites becomes increasingly common in phylogenetic analysis, while heterogeneity among sites arises as one of the major challenges. A single homogeneous model is not sufficient to describe the evolution of all sites and partitioned models are often employed to model the evolution of heterogeneous sites by partitioning them into distinct groups and utilizing distinct evolutionary models for each group. It is crucial to determine the best partitioning, which greatly affects the reconstruction correctness of phylogeny. However, the best partitioning is usually intractable to obtain in practice. Traditional partitioning methods rely on heuristic algorithms or greedy search to determine the best ones in their solution space, are usually time-consuming, and with no guarantee of optimality. In this study, we propose a novel partitioning approach, termed PsiPartition, based on the parameterized sorting indices of sites and Bayesian optimization. We apply our method to empirical data sets and it performs significantly better compared to existing methods, in terms of Bayesian information criterion (BIC) and the corrected Akaike information criterion (AICc). We test PsiPartition on the simulated data sets with different site heterogeneity, alignment lengths, and number of loci. It is demonstrated that PsiPartition evidently and stably outperforms other methods in terms of the Robinson-Foulds (RF) distance between the true simulated trees and the reconstructed trees, especially on the data with more site heterogeneity. More importantly, our proposed Bayesian optimization-based method, for the first time, provides a new general framework to efficiently determine the optimal number of partitions. The corresponding reproducible source code and data are available at http://github.com/xu-shi-jie/PsiPartition.

bioinformatics↗

bioRxiv2024

The Colorado potato beetle gene expression atlas

The Colorado potato beetle (CPB) is a major pest of potato crops that has evolved resistance to more than 50 pesticides. For decades, CPB has been a model species for research on insecticide resistance, insect physiology, diapause, reproduction and evolution. Yet, the research progress in CPB is constrained by the lack of comprehensive genomic and transcriptomic information. Here, building on the recently established chromosome-level genome assembly, we built a gene expression atlas of the CPB using the transcriptomes of 61 samples representing major organs and developmental stages. By using both short and long reads, we improved the genome annotation and identified 6,658 more genes that were missed in previous annotations. We then established a web portal allowing the search and visualization of the gene expression for the research community. The CPB atlas provides useful tools and comprehensive gene expression data, which will accelerate future research in both pest control and insect biology fields.

genomics↗

bioRxiv2024

On the contribution of genetic heterogeneity to complex traits

Genetic heterogeneity, where different alleles or loci are responsible for similar phenotypes, reduces the power of genome-wide association studies and can cause misleading results. Although many striking examples have been identified, the general importance of genetic heterogeneity for complex traits is unclear. Here, we use a novel interpretative machine-learning approach to look for evidence of genetic heterogeneity in plants and humans. Our approach helps identify new loci/alleles influencing trait variation in several agriculturally important species, and we show that at least 6% of maize eQTL, half of them newly identified, exhibit evidence of allelic heterogeneity. Finally, we search for evidence of synthetic associations in human GWAS data, and find that as many as 3-5% may be affected. Our results highlight the need to take genetic heterogeneity seriously, and provide a simple approach for doing so.

genetics↗

bioRxiv2024

Non-invasive and painless mid-infrared modulation increases collagen in human and mouse skin

Stimulating collagen production in skin helps to enhance vitality while decelerating aging- associated processes in skin tissue. However, current approaches to enhancing collagen production are commonly limited by accompanying pain and trauma. Here, we report that mid-infrared modulation (MIMO) at an intensity of 70 mW/cm2 promotes collagen production in human or mouse skin in vivo without generating excessive heat. We found that protein levels of the collagen- degrading endopeptidase, MMP-1, were decreased in the skin of mice following MIMO treatment, whereas the collagen synthesis-related factors, TGF-{beta}, HSP47, and HSP70, were all increased. In addition, MIMO stimulated collagen secretion in human dermal fibroblasts in vitro. This work demonstrates that MIMO is an effective, non-invasive, and painless intervention for in vivo enhancement of collagen production in the skin. One Sentence SummaryMid-infrared modulation promotes collagen production

molecular biology↗

bioRxiv2024

Single-cell genomics and regulatory networks for 388 human brains

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized [~]250 disease-risk genes and drug targets with associated cell types. Summary Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/585576v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@70b24org.highwire.dtl.DTLVardef@6c9eddorg.highwire.dtl.DTLVardef@131fae2org.highwire.dtl.DTLVardef@4e0f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Chemical inhibition of the integrated stress response impairs the ubiquitin-proteasome system

The Integrated Stress Response Inhibitor (ISRIB) is an experimental compound that has been used to explore the potential beneficial effects of reducing the activation of the integrated stress response (ISR). As the ISR is a protective response, there is, however, a risk that its inhibition may compromise the cells ability to restore protein homeostasis. Here, we show that ISRIB treatment impairs degradation of proteins by the ubiquitin-proteasome system (UPS) during proteotoxic stress in the cytosolic, but not nuclear, compartment. Degradation of proteins intercepted by ribosome quality control (RQC) was particularly affected as accumulation of a UPS reporter substrate for ribosome quality control (RQC) was comparable to the level observed after proteasome inhibition. Consistent with impaired RQC, ISRIB treatment caused an accumulation of polyubiquitylated and detergent insoluble defective ribosome products (DRiPs) in the presence of puromycin. As depletion of the RQC ubiquitin ligase listerin partially restored ubiquitin-dependent proteasomal degradation, these data suggest that the persistent protein translation during proteotoxic stress in ISRIB-treated cells increases the pool of newly synthesized proteins targeted by RQC, which aggravates UPS dysfunction by overloading the cytosolic UPS.

cell biology↗

bioRxiv2024

The Rhizobial effector NopT targets Nod factor receptors to regulate symbiosis in Lotus japonicus

It is well-documented that type-III effectors are required by Gram-negative pathogens to directly target different host cellular pathways to promote bacterial infection. However, in the context of legume-rhizobium symbiosis, the role of rhizobial effectors in regulating plant symbiotic pathways remains largely unexplored. Here, we show that NopT, a YopT-type cysteine protease of Sinorhizobium fredii NGR234 directly targets the plants symbiotic signaling pathway by associating with two Nod factor receptors (NFR1 and NFR5 of Lotus japonicus). NopT inhibits cell death triggered by co-expression of NFR1/NFR5 in Nicotiana benthamiana. Full-length NopT physically interacts with NFR1 and NFR5. NopT proteolytically cleaves NFR5 both in vitro and in vivo, but can be inactivated by NFR1 as a result of phosphorylation. NopT plays an essential role in mediating rhizobial infection in L. japonicus. Autocleaved NopT retains the ability to cleave NFR5 but no longer interacts with NFR1. Interestingly, genomes of certain Sinorhizobium species only harbor nopT genes encoding truncated proteins without the autocleavage site. These results reveal an intricate interplay between rhizobia and legumes, in which a rhizobial effector protease targets NFR5 to suppress symbiotic signaling. NFR1 appears to counteract this process by phosphorylating the effector. This discovery highlights the role of a bacterial effector in regulating a signaling pathway in plants and opens up the perspective of developing kinase-interacting proteases to fine-tune cellular signaling processes in general. One-sentence summaryThe rhizobial effector NopT and two Nod factor receptors of Lotus japonicus, NFR1 and NFR5, mutually interact to precisely regulate rhizobial symbiosis.

plant biology↗

bioRxiv2024

Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer

Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCEMechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/583755v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@f07b60org.highwire.dtl.DTLVardef@33ef98org.highwire.dtl.DTLVardef@1b720c8org.highwire.dtl.DTLVardef@1c9514d_HPS_FORMAT_FIGEXP M_FIG Xie et al demonstrate that the polyploid giant cells (PGCs) in the juvenile phase expansion of female bone marrow mesenchymal stromal cells (fBMSCs) can boost neighboring cell proliferation for clonal expansion. However, when fBMSCs enter to the advanced-senescent phase, the dying-senescent PGCs form "spikings" which are then separated into membraned vesicles termed Senescent PGC spiking bodies, SPSBs). The SPSBs carrying fragmented mitochondrial elements and OXPHOS proteins can be phagocytosed by macrophage and breast epithelial cells leading to macrophage aging and breast epithelial protumorigenic transition. The SPSBs are demonstrated to be a new form of post-cell death vesicle from aging BMSCs and may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. C_FIG

cancer biology↗

bioRxiv2024

Impact of alternative splicing on Arabidopsis proteome

Limited proteomic evidence makes it unclear to what extent alternative splicing (AS) isoforms are translated and functionally relevant in eukaryotes. Here, we present a comprehensive proteomic analysis in plants using large-scale data mining, extensive fractionation of AspN-and trypsin-digested proteomes, and both label-free and TMT labeling. In total, we identified 471,196 peptides from 22,479 proteins by searching against Araport11, revealing 32,110 isoform-specific peptides. Using an integrated proteogenomic workflow coupled with SUPPA, we classified these peptides into 2,442 AS events, 879 of which involved intron retention (IR). Further analysis of unannotated events revealed 91 additional IRs that are translated, confirming that retained introns can give rise to peptides. AlphaFold modeling predicted the structural and functional impacts of these isoforms. Our dataset improved existing gene model annotations. By comparing wild-type plants with the AS mutant acinus pinin, we found that IR regulates transcript and protein abundance nonlinearly. Phenotypic assays confirmed the functional consequences, including reduced chlorophyll, impaired growth, and increased anthocyanin. Take together, our results provide large-scale proteomic evidence that AS isoforms are translated in plants, demonstrating how AS diversifies the proteome, regulates protein abundance, and affects growth and development.

plant biology↗

bioRxiv2024

Study of Impacts of Two Types of Cellular Aging on the Yeast Bud Morphogenesis

Understanding the mechanisms of cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short lifespan and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. In this study, by analyzing experimental data it was shown that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional chemical-mechanical model was developed and used to suggest and test hypothesized mechanisms of bud morphogenesis during aging. Experimentally calibrated simulations showed that tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip guided by the polarized Cdc42 signal during the early stage of budding. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage, as observed in experiments, through a reduction on the new cell surface material insertion or an expansion of the polarization site. Thus model simulations suggest the maintenance of new cell surface material insertion or chemical signal polarization could be weakened due to cellular aging in yeast and other cell types. Significance StatementAging yeast exhibits two modes with different bud shapes. Experimental data analysis reveals that control of growth rate and bud size is more robust in cells aging in a spherical budding mode than in cells aging in a tubular budding mode. A computational model was developed and used in combination with experiments to test the hypothesized mechanisms underlying different types of budding in aging cells. Model simulations suggest that localized growth is sufficient to generate tubular budding and its aspect ratio can be stabilized through the regulation of chemical signals with an expanding polarization site or a decline on the new cell surface material insertion. Proposed mechanisms of morphological changes in aging yeast can be present in other cell types.

biophysics↗

bioRxiv2024

ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer's disease.

Multimodal measurements have become widespread in genomics, however measuring open chromatin accessibility and splicing simultaneously in frozen brain tissues remains unconquered. Hence, we devised Single-Cell-ISOform-RNA sequencing coupled with the Assay-for-Transposase-Accessible-Chromatin (ScISOr-ATAC). We utilized ScISOr-ATAC to assess whether chromatin and splicing alterations in the brain convergently affect the same cell types or divergently different ones. We applied ScISOr-ATAC to three major conditions: comparing (i) the Rhesus macaque (Macaca mulatta) prefrontal cortex (PFC) and visual cortex (VIS), (ii) cross species divergence of Rhesus macaque versus human PFC, as well as (iii) dysregulation in Alzheimers disease in human PFC. We found that among cortical-layer biased excitatory neuron subtypes, splicing is highly brain-region specific for L3-5/L6 IT_RORB neurons, moderately specific in L2-3 IT_CUX2.RORB neurons and unspecific in L2-3 IT_CUX2 neurons. In contrast, at the chromatin level, L2-3 IT_CUX2.RORB neurons show the highest brain-region specificity compared to other subtypes. Likewise, when comparing human and macaque PFC, strong evolutionary divergence on one molecular modality does not necessarily imply strong such divergence on another molecular level in the same cell type. Finally, in Alzheimers disease, oligodendrocytes show convergently high dysregulation in both chromatin and splicing. However, chromatin and splicing dysregulation most strongly affect distinct oligodendrocyte subtypes. Overall, these results indicate that chromatin and splicing can show convergent or divergent results depending on the performed comparison, justifying the need for their concurrent measurement to investigate complex systems. Taken together, ScISOr-ATAC allows for the characterization of single-cell splicing and chromatin patterns and the comparison of sample groups in frozen brain samples.

genomics↗

bioRxiv2024

Mechanistic dissection of the CHD4 enhancers reveals cooperative functions among the homotypic ZNF410 clustered motifs

Transcription factors often regulate numerous target genes. However, ZNF410 controls only a single gene, CHD4, in human erythroid cells by its highly restricted chromatin occupancy to the CHD4 locus via two clusters of ZNF410 binding motifs. Here, we uncover that ZNF410 controls chromatin accessibility and activity of the two CHD4 enhancer regions. Combining CRISPR/Cas9 genomic deletion with CRISPRi approaches, we demonstrate that both enhancer regions additively contribute to CHD4 gene expression. Mutations of the di-adenine nucleotides within the ZNF410 binding motif fully disrupt ZNF410-DNA interaction. Luciferase assays, ChIP-seq, and ATAC-seq studies reveal that the homotypic clustered motifs within the CHD4 enhancers are recognized by ZNF410 in a collaborative fashion. Especially, the three ZNF410 motifs located in the 3 end of the distal enhancer act as "switch motifs" to control the chromatin accessibility and activity of the whole distal enhancer region. Together, our findings expose a complex functional hierarchy of motifs, where clustered motifs bound by the same transcription factor cooperate to fine-tune the expression of target gene. HighlightsO_LIZNF410 maintains the accessibility of the CHD4 enhancer regions C_LIO_LIThe two enhancer elements additively modulate CHD4 gene expression C_LIO_LIThe dinucleotide "AA" is the key bases within ZNF410 binding motif C_LIO_LIZNF410 binds to homotypic clustered motifs in a cooperative manner C_LI

molecular biology↗

bioRxiv2024

Laboratory evolution reveals transcriptional mechanisms underlying thermal adaptation of Escherichia coli

Adaptive laboratory evolution (ALE) is able to generate microbial strains which exhibit extreme phenotypes, revealing fundamental biological adaptation mechanisms. Here, we use ALE to evolve Escherichia coli strains that grow at temperatures as high as 45.3{degrees}C, a temperature lethal to wild type cells. The strains adopted a hypermutator phenotype and employed multiple systems-level adaptations that made global analysis of the DNA mutations difficult. Given the challenge at the genomic level, we were motivated to uncover high temperature tolerance adaptation mechanisms at the transcriptomic level. We employed independently modulated gene set (iModulon) analysis to reveal five transcriptional mechanisms underlying growth at high temperatures. These mechanisms were connected to acquired mutations, changes in transcriptome composition, sensory inputs, phenotypes, and protein structures. They are: (i) downregulation of general stress responses while upregulating the specific heat stress responses; (ii) upregulation of flagellar basal bodies without upregulating motility, and upregulation fimbriae; (iii) shift toward anaerobic metabolism, (iv) shift in regulation of iron uptake away from siderophore production, and (v) upregulation of yjfIJKL, a novel heat tolerance operon which we characterized using AlphaFold. iModulons associated with these five mechanisms explain nearly half of all variance in the gene expression in the adapted strains. These thermotolerance strategies reveal that optimal coordination of known stress responses and metabolism can be achieved with a small number of regulatory mutations, and may suggest a new role for large protein export systems. ALE with transcriptomic characterization is a productive approach for elucidating and interpreting adaptation to otherwise lethal stresses.

systems biology↗

bioRxiv2024

Resolving Paradoxes in Molecular Evolution: The Integrated WF-Haldane (WFH) Model of Genetic Drift

Genetic drift, the random changes in frequencies of neutral variants, is the fundamental force of molecular evolution. Under-estimation of genetic drift is a major cause of mis-conclusions on evolution. However, the standard Wright-Fisher (WF) model of random sampling in population of size N only partially defines genetic drift with 1/N or 1/Ne (Ne being a function of varying N's). In parallel, JBS Haldane proposed the branching process for genetic drift (Haldane 1927), whereby each gene copy is transmitted to K descendants with the mean and variance of E(K) and V(K). Genetic drift in its essence is V(K), i.e., the variance in transmission success, or V(K)/N when averaged over the population. Under the general WF models (i.e., the standard model as well as the many modifications), paradoxes have emerged. They include: i) Most curiously, genetic drift may often become stronger as N becomes larger at the ecological time scale, opposite to the model; ii) Sex chromosomes experience drift differently even with the same normalized N; iii) Genetic drift operates on advantageous mutations depends on V(K) but not on N; iv) Irresolution and paradoxes emerge in multi-copy gene systems, including diploidy, viruses and others, whereby evolution progresses both within and between individuals (Wang, et al. 2024). We now show that the integration of the WF and Haldane (i.e., WFH) model can resolve these paradoxes. Most important, the WFH model can fully define genetic drift in molecular evolution.

evolutionary biology↗

bioRxiv2024

Discovery of Alkenyl Oxindole as a Novel PROTAC Moiety for Targeted Protein Degradation via CRL4DCAF11 Recruitment

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of hetero-bifunctional compounds by conjugating different alkenyl oxindoles with the BRD4 inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent hetero-bifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in vivo. Our research provides new employable PROTAC moieties for targeted protein degradation, providing new possibilities for drug discovery.

biochemistry↗