Biology subjects

Luo, K.

Publications and source records attributed to Luo, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Longitudinal imaging of single cells in opaque tissue with cell chirp ultrasound

Small numbers of cells can determine the fate of an entire organism. For example, metastatic cancer cells seed distant organs, therapy-resistant clones repopulate tumors, and T cells infiltrate and expand in tissues with matching antigens. Visualizing the activity of such cells in living organisms requires highly sensitive, specific and repeatable imaging in optically opaque tissues. Here we introduce cell chirp, an ultrasound imaging method for real-time imaging of single cells in living organs inaccessible to light. Cell chirp exploits the harmonic response of genetically encoded gas vesicles to frequency-coded ultrasound to sensitively and specifically visualize single cells in scattering background. We first develop this method in tissue-mimicking phantoms, demonstrating the ability to quantitatively detect single cells as validated by optical cell counts. We then establish the ability of cell chirp to image thousands of genetically labeled cells within a million-cell background tissue, track reporter gene expression over days, and suppress background signals by more than two orders of magnitude. Finally, we use cell chirp to track the fate of antigen-positive or antigen-negative tumor-cell minorities during weeks-long T-cell engager treatments. Cell chirp reveals the dynamics of sparsely distributed, genetically defined cells in opaque tissues.

bioengineering↗

bioRxiv2026

What do satellite vegetation indices actually measure? Photosynthetic capacity rather than transient physiological function across 328 global FLUXNET sites

A direct empirical relationship between gross primary productivity (GPP) estimated by the eddy covariance method and satellite vegetation indices (VIs) has been widely observed across diverse ecosystems globally. Building on this observed covariation, VIs are frequently utilized as critical parameters - such as the fraction of absorbed photosynthetically active radiation (fPAR) - within light use efficiency (LUE) and greenness-based models for carbon cycle monitoring. However, actual canopy carbon assimilation is jointly governed by slowly evolving structural parameters and highly dynamic functional traits, such as physiological efficiency. The extent to which the macro-scale VI-GPP covariance is driven by structural scaffolding, and how this structural signal decouples from physiological function under environmental stress, remains to be systematically quantified. Here, we synthesized half-hourly eddy covariance measurements from 328 globally distributed sites and paired them with a rigorously angle-normalized Enhanced Vegetation Index (nadir view and fixed solar zenith angle at 30 degrees, EVI_SZA30). By applying a nonlinear light-response curve model across 54,720 high-frequency temporal windows, we mechanistically disentangled observed actual GPP (GPP_EC) into baseline photosynthetic capacity (P_c) and intrinsic quantum yield (alpha). Our results demonstrate that the macroscopic covariance between EVI_SZA30 and GPP_EC (R^2=0.554) is primarily driven by the index's robust ability to track structural capacity (P_c, R^2=0.538). In contrast, EVI_SZA30 exhibits limited sensitivity to high-frequency variations in functional traits like physiological efficiency (alpha, R^2=0.038). Particularly in water-limited biomes (e.g., open shrublands and woody savannas), intense environmental stress triggers rapid stomatal regulation while the physical canopy structure remains relatively stable. Consequently, the correlation between EVI and P_c becomes notably stronger than its correlation with actual GPP_EC, highlighting a pronounced structural-physiological decoupling. Because discrete overpasses by sun-synchronous polar-orbiting satellites face intrinsic temporal constraints in capturing sub-daily physiological down-regulation (e.g., midday photosynthetic depression), future monitoring paradigms could greatly benefit from the continuous, high-frequency observations provided by next-generation geostationary (GEO) satellites to bridge the gap between structural parameters and transient ecosystem function.

ecology↗

bioRxiv2026

Elicitation of stem-directed antibodies in rhesus macaques by a conventional hemagglutinin immunogen

Because they can bind many strains of influenza, antibodies targeting the hemagglutinin (HA) stem have been attractive targets for vaccine development. Many monoclonal antibodies (mAbs) directed at the HA stem have been isolated from humans, and these mAbs have mediated broad protection in animal models. We describe here HA stem-directed mAbs isolated from rhesus macaques immunized with an "ordinary" H1 HA trimer. All immunized rhesus macaques developed high serum titers with broad reactivity to diverse H1N1 and H5N1 viruses, and 7 isolated mAbs strongly blocked canonical stem antibody CR6261 binding to H1. MAb DH726.1 robustly protected mice from lethal challenge with H1N1 and H5N1 viruses, and cryo-EM showed the binding footprint overlapped that of some human mAbs. These findings suggest that vaccination with the standard, trimeric HA immunogens may be sufficient to elicit stem antibodies at titers adequate to protect against zoonotic H5N1 influenza. In BriefEfforts to achieve broad influenza protection have largely emphasized increasingly sophisticated immunogen designs to redirect antibody responses toward conserved epitopes. Here, we show that a single, conventional HA immunogen readily elicits antibodies targeting the conserved HA stem, suggesting that routine influenza vaccination may provide broader protection than previously appreciated. HighlightsO_LIMonovalent HA immunization induces strong, stem-directed immune responses in rhesus macaques C_LIO_LIEpitope on the HA stem confirmed by Cryo-EM C_LIO_LIFc-mediated activation of immune effector cell by rhesus-derived stem mAb C_LIO_LIHA stem-directed antibody protects mice against H1N1 and H5N1 viruses C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/738984v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1535b59org.highwire.dtl.DTLVardef@192422dorg.highwire.dtl.DTLVardef@136b3d5org.highwire.dtl.DTLVardef@586fd4_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

In vivo spatial coordination with synthetic paracrine signaling

The immune system uses paracrine signaling to spatially confine potent responses such as inflammation. A bio-orthogonal synthetic paracrine system could enable engineering of analogous multicellular circuits in which different cell types coordinate their functions in a spatially organized fashion. Here, using the plant hormone auxin as a bio-orthogonal chemical signal, we introduce programmable paracrine circuits that distribute sensing and effector functions to different cell types to spatially restrict responses in mouse xenografts. Cells engineered to express auxin biosynthetic genes generated auxin-dense regions with tunable length scales in vivo. This localized signaling ability enabled design of a multicellular sentinel-effector system, in which THP-1 sentinel cells conditionally produce auxin in regions expressing the tumor-specific antigen EGFRvIII, and Jurkat effector cells respond by locally modulating the activity of a chimeric antigen receptor (CAR). This two-cell type system was able to achieve localized activation of engineered effector cells in vivo. These results establish a foundation for engineering multicellular therapeutic systems that focus responses in specific tissue contexts or disease sites.

Synthetic Biology↗

bioRxiv2026

Rapid Determination of Drug-to-Antibody Ratios in Antibody Drug Conjugates Using Ultrafast Microdroplet Digestion Technology

Accurate determination of drug-to-antibody ratios (DARs) is essential for the development, quality control, and performance evaluation of antibody-drug conjugates (ADCs); yet conventional analytical approaches often require extensive sample preparation, long analysis time, and substantial sample consumption. The peak distribution of intact ADCs is highly complex due to inherent glycosylation heterogeneity and variable drug conjugation. By applying enzymatic digestion, ADC can be converted into smaller subunits or deglycosylated species, thereby significantly simplifying the mass spectral profile. This reduction in structural heterogeneity facilitates clearer peak assignment and enables more accurate and reliable DAR quantification. Herein, we report an ultrafast microdroplet digestion-mass spectrometry strategy for rapid DAR characterization of ADCs. Microdroplet enzymatic digestion of antibodies and ADCs occurs within microsecond-time scales during spray ionization, enabling direct online subunit analysis with minimal sample preparation. The method was validated using NIST monoclonal antibody (mAb) conjugated to ADC mimics spanning low to high DAR (0-14) ranges, Cetuximab-derived ADC mimics (DAR[~]5) with complex glycosylation, and the commercial ADC Kadcyla (DAR[~]3.5). Consistent DAR values were obtained across multiple enzymatic workflows (IdeS, EndoS2, and EndoF3) with good reproducibility (%CV typically <5%). This approach substantially reduces analysis time while maintaining analytical accuracy and structural specificity, providing a rapid, sensitive platform for high-throughput ADC characterization and process monitoring. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/729562v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@23145corg.highwire.dtl.DTLVardef@10ddd88org.highwire.dtl.DTLVardef@14b1370org.highwire.dtl.DTLVardef@1e94ad6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

PRMT7 restricts CD8+ T cells expansion via the NF-κB pathway.

New therapeutics are needed to enhance cytotoxic T lymphocyte (CTL) expansion and effector function for effective tumor control. Here, we show that T cell specific deletion of Prmt7 using CD4-Cre mice increases CD8+ effector differentiation, cytokine secretion, cytolytic activity, and anti-tumor responses. Prmt7 deficiency transcriptionally reprogrammed CD8+ T cells by activating the NF-{kappa}B pathway, boosting proliferation, and elevating effector molecules such as CD25, CD69, and IFN{gamma}. Mechanistically, PRMT7 associated with RelA and restricted its nuclear translocation. To enable therapeutic translation, we developed a PRMT7-targeting PROTAC degrader (MS54). MS54-treated CTLs exhibited NF-{kappa}B pathway activation similar to Prmt7-deficient CTLs. Adoptive transfer of MS54-treated OT-I CTLs significantly improved tumor control in a syngeneic melanoma model. In human CTLs, MS54 enhanced proliferation, activation markers (CD69, CD137), IFN{gamma} production, and cytotoxicity toward melanoma. Together, these findings identify PRMT7 as a negative regulator of CD8+ T cell immunity and highlight MS54 as a promising strategy to improve adoptive T cell therapy.

molecular biology↗

bioRxiv2026

The ENL-USP7 Complex Regulates HIV Latency Through BRD4 Stabilization

HIV-1 persists in CD4 T cells and brain microglia through host factors that enforce viral latency, yet the mechanisms that stabilize key transcriptional regulators remain incompletely understood. Here, we identify the YEATS domain-containing protein ENL and its associated deubiquitinase USP7 as a host complex that maintains HIV-1 latency. USP7 stabilizes BRD4 by deubiquitination, suppressing HIV transcription and sustaining viral quiescence. Disruption of the ENL-USP7 complex using selective PROTACs reactivates latent HIV in cell line models, as well as in resting CD4 T cells and microglia isolated from people with HIV on antiretroviral therapy. These findings uncover a critical ENL-USP7-BRD4 axis that enforces HIV-1 latency and highlight USP7 as a potential target for latency-reversing strategies. HighlightsO_LIENL, a YEATS domain-containing crotonylation reader, acts as a suppressor rather than an activator of HIV-1 transcription. C_LIO_LIENL recruits USP7 to stabilize BRD4 and enforce viral latency. C_LIO_LIDisruption of the ENL-USP7-BRD4 axis reactivates latent HIV in T cells and microglia. C_LIO_LITargeting USP7 or ENL reveals a therapeutic vulnerability in HIV reservoirs. C_LI

microbiology↗

bioRxiv2026

Analysis of the assembly, stabilization and maturation of the multiphasic TAZ biomolecular condensates

Phase separation is an important mechanism ensuring efficient regulation and function in Hippo signaling. Particularly, phase separation of nuclear TAZ has been demonstrated to be essential for its activity. However, the mechanisms of TAZ condensate assembly and maturation are yet undefined. Here we explored these mechanisms using FRAP with two laser beam sizes complemented by microscopy and cell biology approaches. We show that TAZ condensates are multiphasic, with a more stable core and labile periphery. TAZ initially forms small nascent clusters, likely via self-nucleation through the CC domain. These gradually mature into larger condensates through interaction with additional proteins via the WW domain. The condensates are further stabilized/activated by interaction with transcription factors and complexes including TEAD4 and P-TEFb. Of note, the ability of TAZ to form mature condensates is essential for its activities in cellular morphogenesis and tumorigenesis. Our study presents detailed mechanistic analysis of TAZ phase separation, revealing a highly dynamic nature of TAZ condensate maturation and activation. TeaserTAZ condensates grow from nascent clusters into mature condensates by interactions with transcription factors and complexes.

cell biology↗

bioRxiv2025

Water body size shapes body size evolution via subgenomic selection in allopolyploid fish

Allopolyploidization is a major force in species evolution, and studying allopolyploids in diverse environments provides insights into their genetic mechanisms. Here, we investigated how water body size variation influences body size in allopolyploid fish. We used a nascent allopolyploid lineage derived from goldfish (Carassius auratus) and common carp (Cyprinus carpio) and established two populations in small and large water bodies for two generations. Genomic, transcriptomic, and epigenomic analyses revealed that the larger population had higher genetic diversity in subgenome R, while the smaller population had higher diversity in subgenome C. Potential selection regions were associated with growth regulatory genes, suggesting a role for gene regulation in body size adaptation. Dynamic gene expression patterns in various tissues indicated potential mechanisms underlying muscle development and adaptation to smaller water bodies. Furthermore, selection regions were linked to changes in chromatin accessibility, with subgenome R being more susceptible to these changes during genetic divergence. Our findings demonstrate that water body size variation drives body size in allopolyploid fish through subgenomic selection, impacting genetic variation, gene regulation, and epigenetic mechanisms.

genomics↗

bioRxiv2024

Shade Inhibits Cambial Activity in Populus Stems by the SPL16/SPL23-Mediated Cytokinin Pathway

Trees in natural forests or plantations often encounter neighbor proximity signal that negatively impacts wood production. However, the molecular basis underlying shade-regulation of vascular cambial activity during stem radial growth remains unknown in woody species. Here, we revealed that high stand density and simulated shade (low R/FR ratio) suppress the division and differentiation of cambial cells in poplar stems. A genome-wide screen for Populus SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes identified that SPL16 and SPL23 are preferentially expressed in the phloem and cambium, being downregulated by simulated shade. Knocking out SPL16/23 impaired cambial activity, whereas phloem-specific overexpression of SPL16 stimulated cambial proliferation and mitigated the shade-inhibition of cambial activity. Additionally, shade decreased bioactive cytokinin (CK) levels by suppressing the expression of CK biosynthesis genes IPT5a, IPT5b and LOG1b in poplar stems. Molecular and genetic studies reveled that SPL16/23 directly activate IPT5s/LOG1b expression to promote CK biosynthesis and cambial activity. Moreover, elevated miR156 expression in shade-treated stems regulated SPL16/23 at the post-transcriptional level, mediating shades effects on cambial activity. Collectively, our findings unravel that the miR156-SPL16/23-IPT5/LOG1-cytokinin pathway operates in the shade-mediated inhibition of cambial activity, providing potential targets for the genetic improvement of shade-tolerant trees.

plant biology↗

bioRxiv2024

Phosphodiesterase 1A physically interacts with YTHDF2 and reinforces the progression of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of PDE1A in NSCLC. The RIP assay, mRNA stability assay and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. Phosphodiesterase 1A (PDE1A) has been shown to promote metastasis and EMT progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpresssed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of YTHDF2/PDE1A complex in regulating STAT3 pathway was predicted by overlapping YTHDF2-interacting-RNAs, and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated STAT3 pathway. The data not only uncovers a novel PDE1A/YTHDF2/STAT3 pathway in NSCLC progression but also provides therapeutic strategies for treating NSCLC patients with metastasis.

cancer biology↗

bioRxiv2024

Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimers disease (AD), contributing to the accumulation of amyloid-{beta} (A{beta}) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the A{beta} transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces A{beta} deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated A{beta} clearance in mitigating disease progression.

neuroscience↗

bioRxiv2024

Variation and interaction of distinct subgenomes contribute to growth diversity in intergeneric hybrid fish

Intergeneric hybridization greatly reshapes regulatory interactions among allelic and non-allelic genes. However, their effects on growth diversity remain poorly understood in animals. In this study, we conducted whole-genome sequencing and mRNA-seq analyses in diverse hybrid varieties resulting from the intergeneric hybridization of goldfish (Carassius auratus red var.) and common carp (Cyprinus carpio). These hybrid individuals were characterized by distinct mitochondrial genomes and copy number variations. Through a weighted gene correlation network analysis, we identified 3693 genes as candidate growth-regulated genes. Among them, the expression of 3672 genes in subgenome R (originating from goldfish) displayed negative correlations with growth rate, whereas 20 genes in subgenome C (originating from common carp) exhibited positive correlations. Notably, we observed intriguing patterns in the expression of slc2a12 in subgenome C, showing opposite correlations with body weight that changed with water temperatures, suggesting differential interactions between feeding activity and weight gain in response to seasonal changes for hybrid animals. In 40.31% of alleles, we observed dominant trans-regulatory effects in the regulatory interaction between distinct alleles from subgenomes R and C. Integrating analyses of allelic-specific expression and DNA methylation data revealed that the influence of DNA methylation on both subgenomes shapes the relative contribution of allelic expression to the growth rate. These findings provide novel insights into the interaction of distinct subgenomes that underlie heterosis in growth traits and contribute to a better understanding of multiple-allele traits in animals.

genetics↗

bioRxiv2024

RegionScan: A comprehensive R package for region-level genome-wide association testing with integration and visualization of multiple-variant and single-variant hypothesis testing

SummaryRegionScan is an R package for comprehensive and scalable genome-wide association testing of region-level multiple-variant and single-variant statistics and visualization of the results. It implements various state-of-the-art region-level tests to improve signal detection under heterogeneous genetic architectures and facilitates comparison of multiple-variant region-level and single-variant test results. It exploits local linkage disequilibrium (LD) structure for genomic partitioning and LD-adaptive region definition. RegionScan is compatible with VCF input file formats for genotyped and imputed variants, and options are available for analysis of multi-allelic variants and unbalanced binary phenotypes. It accommodates parallel region-level processing and analysis to improve computational time and memory efficiency and provides detailed outputs and utility functions to assist results comparison, visualization, and interpretation. Availability and implementationRegionScan is freely available for download on GitHub (https://github.com/brossardMyriam/RegionScan). Contactbull@lunenfeld.ca, brossard@lunenfeld.ca. Supplementary informationSupplementary data are available at Bioinformatics online.

genetics↗

bioRxiv2024

Zebrafish live imaging reveals only around 2% rather than 50% of motor neurons die through apoptosis during development

It is widely accepted that large numbers of neurons die during the early development of vertebrates; however, the tracking of this dying process in live animals remains challenging. Here, we generated sensor zebrafish achieving live imaging of motor neuron apoptosis at single- cell resolution. Using these sensor zebrafish, we observed for the first time that in an apoptotic motor neuron, caspase-3 activation occurred quickly within 5-6 min and at the same time between the cell body and axon. Interestingly, we found that only a surprisingly small percentage of spinal cord motor neurons died during zebrafish early development, which is quite different from the generally believed massive motor neuron death occurred in the embryonic stage of chicks, mice, rats, and humans. We also observed that most of the apoptotic bodies of dead motor neurons were not colocalized with macrophages. These sensor zebrafish can serve as powerful tools to study motor neuron apoptosis in vivo.

neuroscience↗

bioRxiv2023

Single cell analyses of cancer cells identified two regulatorily and functionally distinct categories in differentially expressed genes among tumor subclones

To explore the feature of cancer cells and tumor subclones, we analyzed 101,065 single-cell transcriptomes from 12 colorectal cancer (CRC) patients and 92 single cell genomes from one of these patients. We found cancer cells, endothelial cells and stromal cells in tumor tissue expressed much more genes and had stronger cell-cell interactions than their counterparts in normal tissue. We identified copy number variations (CNVs) in each cancer cell and found correlation between gene copy number and expression level in cancer cells at single cell resolution. Analysis of tumor subclones inferred by CNVs showed accumulation of mutations in each tumor subclone along lineage trajectories. We found differentially expressed genes (DEGs) between tumor subclones had two populations: DEGCNV and DEGreg. DEGCNV, showing high CNV-expression correlation and whose expression differences depend on the differences of CNV level, enriched in housekeeping genes and cell adhesion associated genes. DEGreg, showing low CNV-expression correlation and mainly in low CNV variation regions and regions without CNVs, enriched in cytokine signaling genes. Furthermore, cell-cell communication analyses showed that DEGCNV tends to involve in cell-cell contact while DEGreg tends to involve in secreted signaling, which further support that DEGCNV and DEGreg are two regulatorily and functionally distinct categories.

genomics↗

bioRxiv2023

Interpreting structure in sequence count data with differential expression analysis allowing for grades of membership

Parts-based representations, such as non-negative matrix factorization and topic modeling, have been used to identify structure from single-cell sequencing data sets, in particular structure that is not as well captured by clustering or other dimensionality reduction methods. However, interpreting the individual parts remains a challenge. To address this challenge, we extend methods for differential expression analysis by allowing cells to have partial membership to multiple groups. We call this grade of membership differential expression (GoM DE). We illustrate the benefits of GoM DE for annotating topics identified in several single-cell RNA-seq and ATAC-seq data sets.

genomics↗

bioRxiv2022

Targeted degradation of PRC1 components, BMI1 and RING1B, via a novel protein complex degrader strategy

Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono-ubiquitination (H2AK119ub). BMI1 and RING1B are PRC1 core components and play critical roles in the development of various cancers. However, therapeutic agents targeting PRC1 are very limited, and small-molecule inhibitors of PRC1 displayed limited effectiveness in killing cancer cells. In this study, MS147, the first degrader of PRC1 core components, BMI1 and RING1B, was discovered via a novel protein complex degradation strategy that utilizes the target proteins interacting partner protein (EED) to degrade BMI1 and RING1B. MS147, which comprises an EED small-molecule binder linked to a ligand of the E3 ligase VHL, degrades BMI1 and RING1B in an EED-, VHL-, ubiquitination- and time-dependent manner. MS147 is selective and preferentially degrades BMI1 and RING1B over PRC2 core components: EED, EZH2 and SUZ12. Consequently, MS147 effectively reduces H2AK119ub, but not H3K27me3, which is catalyzed by PRC2. Furthermore, MS147, but not the parent EED binder or known PRC2 degraders, effectively inhibits the proliferation of cancer cell lines that are insensitive to EZH2 knockout or PRC2 degraders. Overall, this study provides a novel degrader targeting BMI1 and RING1B, which is a useful chemical tool to further investigate the roles of PRC1 in cancer, and a novel protein complex degradation strategy, which could potentially expand the degradable human proteome.

biochemistry↗