Biology subjects

Gong, Y.

Publications and source records attributed to Gong, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

RGAST: Relational Graph Attention Network for Spatial Transcriptome Analysis

Cell-cell communication (CCC) plays a fundamental role in tissue organization and function. Recent advances in spatial transcriptomics (ST) technologies have enabled high-resolution mapping of CCC at single-cell level. However, existing computational approaches for CCC inference face several limitations, including reliance on predefined ligand-receptor databases, loss of single-cell resolution, and inability to model long range communications. To address these challenges, we developed RGAST, a deep learning framework that integrates both spatial proximity and transcriptional profiles to reconstruct multi-scale CCC networks de novo. In our analysis, RGAST revealed directional communication from peripheral to central nuclei in mouse hypothalamus and tumor invasion signaling axis in breast cancer. Leveraging a relational graph attention network, RGAST effectively captures both local and global communication patterns while learning low-dimensional representations of ST data, which are versatile in multiple downstream tasks. Our results demonstrate that RGAST enhances spatial domain identification accuracy by approximately 10% compared to the second method in 10X Visium DLPFC dataset. Furthermore, RGAST facilitates the discovery of spatially variable genes, enables more precise cell trajectory inference and reveals intricate 3D spatial patterns across multiple sections of ST data.

bioinformatics↗

bioRxiv2024

Unveiling Fine-scale Spatial Structures and Amplifying Gene Expression Signals in Ultra-Large ST slices with HERGAST

We propose HERGAST, a system for spatial structure identification and signal amplification in ultra-large-scale and ultra-high-resolution spatial transcriptomics data. To handle ultra-large ST data, we consider the divide and conquer strategy and devise a Divide-Iterate-Conque framework specially for spatial transcriptomics data analysis, which can also be adopted by other computational methods for extending to ultra-large-scale ST data analysis. To tackle the potential oversmoothing problem arising from data splitting, we construct a heterogeneous graph network to incorporate both local and global spatial relationships. In simulation, HERGAST consistently outperformed other methods across all settings with more than 10% average gaining. In real-world data, HERGASTs high-precision spatial clustering enabled finding SPP1+ macrophages intermingled in tumors in colorectal cancer, while the enhanced gene expression signal enabled discovering unique spatial expression pattern of key genes in breast cancer.

bioinformatics↗

bioRxiv2024

Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners

ObjectiveDysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context. MethodsWe used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth. ResultsInhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice. ConclusionOur findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.

cell biology↗

bioRxiv2024

Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism

Approximately 40% ER-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ER level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ER at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre+; Frmd8fl/fl; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ER. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1. On the other hand, FRMD8 interacts both with ER and UBE3A, and disrupts the interaction of UBE3A with ER, thereby blocking UBE3A-mediated ER degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ER and may control therapeutic sensitivity to tamoxifen in ER-positive breast cancer patients. Impact StatementTumor suppressive protein FRMD8 inhibits breast cancer progression by regulating the level of ER and has the possibility to be a potential target for overcoming tamoxifen treatment resistance.

cancer biology↗

bioRxiv2024

CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis

Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy. However, a substantial proportion of patients either do not respond or develop resistances. This underscores a need for novel approaches and therapeutic targets as well as a better understanding of the mechanisms of melanoma pathogenesis. Long non-coding RNAs (lncRNAs) comprise a poorly characterized class of functional players and promising targets in promoting malignancy. Certain lncRNAs have been identified to play integral roles in melanoma progression and drug resistances, however systematic screens to uncover novel functional lncRNAs are scarce. Here, we profile differentially expressed lncRNAs in patient derived short-term metastatic cultures and BRAF-MEK-inhibition resistant cells. We conduct a focused growth-related CRISPR-inhibition screen of overexpressed lncRNAs, validate and functionally characterize lncRNA hits with respect to cellular growth, invasive capacities and apoptosis in vitro as well as the transcriptomic impact of our lead candidate the novel lncRNA XLOC_030781. In sum, we extend the current knowledge of ncRNAs and their potential relevance on melanoma. SignificancePreviously considered as transcriptional noise, lncRNAs have emerged as novel players in regulating many cellular aspects in health and disease including melanoma. However, the number and as well as the extent of functional significance of most lncRNAs remains elusive. We provide a comprehensive strategy to identify functionally relevant lncRNAs in melanoma by combining expression profiling with CRISPR-inhibition growths screens lowering the experimental effort. We also provide a larger resource of differentially expressed lncRNAs with potential implications in melanoma growth and invasion. Our results broaden the characterized of lncRNAs as potential targets for future therapeutic applications.

cancer biology↗

bioRxiv2024

Enhancing Whole Slide Image Classification with Discriminative and Contrastive Learning

Whole slide image (WSI) classification plays a crucial role in digital pathology data analysis. However, the immense size of WSIs and the absence of fine-grained sub-region labels, such as patches, pose significant challenges for accurate WSI classification. Typical classification-driven deep learning methods often struggle to generate compact image representations, which can compromise the robustness of WSI classification. In this study, we address this challenge by incorporating both discriminative and contrastive learning techniques for WSI classification. Different from the extant contrastive learning methods for WSI classification that primarily assign pseudo labels to patches based on the WSI-level labels, our approach takes a different route to directly focus on constructing positive and negative samples at the WSI-level. Specifically, we select a subset of representative and informative patches to represent WSIs and create positive and negative samples at the WSI-level, allowing us to better capture WSI-level information and increase the likelihood of effectively learning informative features. Experimental results on two datasets and ablation studies have demonstrated that our method significantly improved the WSI classification performance compared to state-of-the-art deep learning methods and enabled learning of informative features that promoted robustness of the WSI classification.

pathology↗

bioRxiv2024

Delta-5 elongase knockout reduces DHA and TAG synthesis coupled with an increase of heat sensitivity in a marine diatom

Recent global marine lipidomic analysis reveals a strong relationship in the ocean between temperature and phytoplanktonic abundance of omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are essential for human nutrition and primarily from phytoplankton in marine food webs. In phytoplanktonic organisms, EPA may play a major role in regulating the phase transition temperature of membranes, while the function of DHA remains to be explored. In the oleaginous diatom Phaeodactylum tricornutum, DHA is distributed mainly on extraplastidial phospholipids, which is very different from the EPA enriched in thylakoid lipids. Here, CRISPR/Cas9-mediated knockout of ptELO5a, which encodes a delta-5 elongase catalyzing the elongation of EPA to synthesize DHA, led to a substantial interruption of DHA synthesis in P. tricornutum. The ptELO5a mutants show significant alterations in transcriptome and glycerolipidomes including membrane lipids and triacylglycerols under normal temperature (22{degrees}C), and are more sensitive to elevated temperature (28{degrees}C) than wild type. We conclude that the PtELO5a-mediated synthesis of small amounts of DHA has indispensable functions in regulating the membrane lipid, and indirectly contributing storage lipid accumulation and maintaining thermomorphogenesis in P. tricornutum. This study also highlights the significance of DHA synthesis and lipid composition for environmental adaptation of P. tricornutum.

plant biology↗

bioRxiv2024

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called "noncanonical" autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly in ATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment. Key messagesO_LIPolymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLE C_LIO_LIWhile autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SSc C_LIO_LIWe show here that autophagy is comparable between PBMCs from patients and matched controls C_LIO_LIWe find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patients C_LIO_LIAs LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation C_LI

immunology↗

bioRxiv2024

Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer

Magnesium (Mg) deficiency is associated with increased risk and malignancy of colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomics and phosphoproteomics indicated that low tumorous Mg content may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which, in turn, enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may offer a promising preventive and therapeutic strategy for CRC.

cancer biology↗

bioRxiv2024

Genomic evidence for supergene control of Darwin's 'complex marriage arrangement' - the tristylous floral polymorphism

Tristyly is a polymorphism characterized by three flower morphs with reciprocal stigma and anther heights controlled by two epistatically interacting diallelic loci (S and M), hypothesized to be supergenes. Chromosome-level genome assemblies of Eichhornia paniculata identified the S- and M-loci. The S-locus is a supergene consisting of two divergent alleles: The S-allele (2.51Mb) with three S-allele specific genes hemizygous in most S-morph plants and the s-allele (596kb) with five s-allele specific genes. Two of the S-allele specific genes, LAZY1-S and HRGP-S, were specifically expressed in styles and stamens, respectively, making them tristyly candidate genes. The M-locus contained one gene (LAZY1-M), homologous to LAZY1-S, that was present in the M-allele but absent from the m-allele. Estimates of allele ages are consistent with the prediction that the S-locus evolved before the M-locus. Re-use of the same gene family highlights the potential role of gene duplication in the evolution of epistatic multilocus polymorphisms.

evolutionary biology↗

bioRxiv2023

Phylogenomics resolves key relationships in Rumex and uncovers a dynamic history of independently evolving sex chromosomes

Sex chromosomes have evolved independently many times across eukaryotes. Despite a considerable body of literature on the evolution of sex chromosomes, the causes and consequences of variation in the formation, degeneration, and turnover of sex chromosomes remain poorly understood. Comparative approaches in groups with sexual system variation can be valuable for understanding these questions. Plants are well-suited to such comparative studies, with many lineages containing relatively recent origins of dioecy and sex chromosomes as well as hermaphroditic close relatives. Rumex is a diverse genus of flowering plants harboring significant sexual system variation, including hermaphroditic and dioecious clades with XY sex chromosomes. Previous disagreement in the phylogenetic relationships among key species have rendered the history of sex chromosome evolution uncertain. Resolving this history is important to the development of Rumex as a system for the comparative study of sex chromosome evolution. Here, we leverage new transcriptome assemblies from 11 species representing the major clades in the genus, along with a whole-genome assembly generated for a pivotal hermaphroditic species, to further resolve the phylogeny and history of sex chromosome evolution in Rumex. Using phylogenomic approaches, we find evidence for two independent origins of sex chromosomes and introgression from unsampled taxa in the genus. Comparative genomics reveals massive chromosomal rearrangements in a dioecious species, with evidence for a complex origin of the sex chromosomes through multiple chromosomal fusions. However, we see no evidence of elevated rates of fusion on the sex chromosome in comparison with autosomes, providing no support for an adaptive hypothesis for the sex chromosome expansion. Overall, our results highlight the dynamic nature of sex chromosome systems in Rumex and illustrate the utility of the genus as a model for the comparative study of sex chromosome evolution.

evolutionary biology↗

bioRxiv2023

Nuclear cytoophidia assembly represses transcriptional activity to control skeletal development and homeostasis

Compartmentation via filamentation is an evolutionarily conserved subcellular structure that fine-tunes the inherent activity of proteins. Cytoophidia represent a typical class of filamentous structures controlling enzymatic activities. Despite eukaryotic cells containing both cytoplasmic cytoophidia and nuclear cytoophidia, the physiological significance of nuclear cytoophidia is largely unknown. Here we show that nuclear filamentation inhibits the transcriptional activity of Impdh2 required for limb formation and bone resorption. Impdh2 deletion in mouse limb mesenchymal progenitors causes severe skeletal dysplasia by impairing endochondral ossification and chondrocyte differentiation. Additionally, Impdh2 deficiency in myeloid lineages leads to an increased bone mass via impeding osteoclast differentiation. Furthermore, Impdh2 regulates osteoclastic mitochondrial biogenesis and function. We propose that the nuclear compartmentalization of Impdh2 regulates the transcriptional activity during skeletal development and homeostasis.

cell biology↗

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

Presence of NCOR1+/CD4+ T cells in tertiary lymphoid organ predicts favorable prognosis in pancreatic ductal adenocarcinoma

CD4+ T cells have critical roles in anti-tumour immunity and its differentiation is known to be regulated by the nuclear receptor co-repressor 1 (NCOR1). Previous studies suggested that high CD4+ T cells are associated with a favourable prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of NCOR1 in PDAC is still missing. In this study, the pathological impact of NCOR1 and CD4 has been analysed by multiplex immunohistochemistry in 100 PADC patients. NCOR1 expression in tertiary lymphoid organs is positively associated with the good prognosis of PDAC patients, while its expression in tumour tissue is not. Furthermore, the presence of NCOR1+/CD4+ T cells in tertiary lymphoid organs predicts a favourable prognosis in PDAC. Mechanistically, upregulation of NCOR1 expression in CD4+ T cells increases the release of TNF-, which induces the apoptosis of the tumor cells in vitro. Together, our data highlighted the tumour suppressive role of NCOR1+/CD4+ T cells in PDAC.

cancer biology↗

bioRxiv2023

Phased assembly of neo-sex chromosomes reveals extensive Y degeneration and rapid genome evolution in Rumex hastatulus

Y chromosomes are thought to undergo progressive degeneration due to stepwise loss of recombination and subsequent reduction in selection efficiency. However, the timescales and evolutionary forces driving degeneration remain unclear. To investigate the evolution of sex chromosomes on multiple timescales, we generated a high-quality phased genome assembly of the massive older (<10MYA) and neo (<200,000 years) sex chromosomes in the XYY cytotype of the dioecious plant Rumex hastatulus and a hermaphroditic outgroup R. salicifolius. Our assemblies, supported by fluorescence in situ hybridization, confirmed the neo-sex chromosomes were formed by two key events: an X-autosome fusion and a reciprocal translocation between the homologous autosome and the Y chromosome. The enormous sex-linked regions of the X (296 MB) and two Y chromosomes (503 MB) both evolved from large repeat-rich genomic regions with low recombination; however, the complete loss of recombination on the Y still led to over 30% gene loss and major rearrangements. In the older sex-linked region, there has been a significant increase in transposable element abundance, even into and near genes. In the neo sex-linked regions, we observed evidence of extensive rearrangements without gene degeneration and loss. Overall, we inferred significant degeneration during the first 10 million years of Y chromosome evolution but not on very short timescales. Our results indicate that even when sex chromosomes emerge from repetitive regions of already-low recombination, the complete loss of recombination on the Y chromosome still leads to a substantial increase in repetitive element content and gene degeneration.

evolutionary biology↗

bioRxiv2023

In vivo selection in non-human primates identifies superior AAV capsids for on-target CSF delivery to spinal cord

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal delivery of AAV vectors into the cerebral spinal fluid (CSF) can avoid many of the issues of systemic delivery, although achieving broad distribution of the vector and transgene expression throughout the spinal cord is challenging and vector entry to the periphery occurs, sometimes initiating hepatotoxicity. Here we performed two rounds of in vivo biopanning in non-human primates (NHPs) with an AAV9 peptide display library injected intrathecally and performed insert sequencing on DNA isolated from either whole tissue (conventional selection), isolated nuclei, or nuclei from transgene-expressing cells. A subsequent barcoded pool of candidates and AAV9 was compared at the DNA (biodistribution) and RNA (expression) level in spinal cord and liver of intrathecally injected NHPs. Most of the candidates displayed enhanced biodistribution compared to AAV9 at all levels of spinal cord ranging from 2 to 265-fold. Nuclear isolation or expression-based selection yielded 4 of 7 candidate capsids with enhanced transgene expression in spinal cord (up to 2.4-fold), while no capsid obtained by conventional selection achieved that level. Furthermore, several capsids displayed lower biodistribution to the liver of up to 1,250-fold, compared to AAV9, providing a remarkable on target/off target biodistribution ratio. These capsids may have potential for gene therapy programs directed at the spinal cord and the selection method described here should be useful in clinically relevant large animal models.

bioengineering↗

bioRxiv2023

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has a remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signaling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

immunology↗

bioRxiv2023

Mecp2 Fine-tunes Quiescence Exit by Targeting Nuclear Receptors

Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit, as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. Genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly, disruption of two nuclear receptors (NRs), Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.

cell biology↗