Biology subjects

Xue, H.

Publications and source records attributed to Xue, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimers Disease

SUMMARYWhile challenging, identifying individuals displaying resilience to Alzheimers disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.

neuroscience↗

bioRxiv2024

In sickness and in health: RNA-Seq finds viruses associated with mutualist quality in the Amazonian plant-ant Allomerus octoarticulatus

Ant-plant symbioses are classic examples of mutualism in which ant "bodyguards" defend myrmecophytic plants against enemies in exchange for nest sites and often food. We used RNA-Seq to profile the transcriptomes of Allomerus octoarticulatus ant workers, which aggressively defend the Amazonian plant Cordia nodosa against herbivores, but to varying degrees. Field behavioral assays with herbivores in the Peruvian Amazon showed striking variation among colonies in the relative zeal with which A. octoarticulatus workers defend their host plant. Highly effective and ineffective bodyguards differed in their gene expression profiles, which revealed viral infections significantly associated with ant bodyguarding behavior. Transcripts from eight new positive-sense single-stranded RNA viruses were differentially expressed between colonies with high- or low-quality bodyguards. Colonies of high- and low-quality bodyguards were infected by distinct viruses, including viruses clustering phylogenetically with viruses known to cause aggression or reduced locomotion, respectively, in bees. Gene expression, including of immunity-related genes, also differed between broodcare workers and bodyguard ants, suggesting bodyguarding is a distinct worker task. Ant colony health and viral infections may influence ant cooperation with plants in ant-plant mutualisms. Significance statementMany animals have evolved to cooperate with plants in plant-animal mutualisms, including in pollination, seed dispersal, and defensive ant-plant interactions. Although the ecology of these interactions is well studied, little is known about the molecular mechanisms involved in animal cooperation with plants. Studying an Amazonian ant-plant symbiosis, we combined field assays of ant behavior with RNA-Seq to profile the transcriptomes of ants that vary in their quality as defensive plant "bodyguards." Bodyguard ants that effectively defended plants against herbivores expressed different genes than both ineffective bodyguards and broodcare workers. Surprisingly, many genes differentially expressed between high- and low-quality bodyguards were from viruses, and not ants. Thus, we linked viral infections to mutualist quality in this ant-plant symbiosis.

ecology↗

bioRxiv2024

Exploring a large cancer cell line RNA-sequencing dataset with k-mers

Analyzing the immense diversity of RNA isoforms in large RNA-seq repositories requires laborious data processing using specialized tools. Indexing techniques based on k-mers have previously been effective at searching for RNA sequences across thousands of RNA-seq libraries but falling short of enabling direct RNA quantification. We show here that RNAs queried in the form of k-mer sets can be quantified in seconds, with a precision akin to that of conventional RNA quantification methods. We showcase several applications by exploring an index of the Cancer Cell Line Encyclopedia (CCLE) collection consisting of 1019 RNA-seq samples. Non-reference RNA sequences such as RNAs harboring driver mutations and fusions, splicing isoforms or RNAs derived from repetitive elements, can be retrieved with high accuracy. Moreover, we show that k-mer indexing offers a powerful means to reveal variant RNAs induced by specific gene alterations, for instance in splicing factors. A web server allows public queries in CCLE and other indexes: https://transipedia.fr. Code is provided to allow users to set up their own server from any RNA-seq dataset.

bioinformatics↗

bioRxiv2024

Loss of function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

PurposeEpigenetic dysregulation has been associated with many inherited disorders. RBBP5 encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. MethodsWe identify five unrelated individuals with de novo heterozygous pathogenic variants in RBBP5. Three truncating and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. ResultsBoth missense p.T232I and p.E296D variants affect evolutionarily conserved amino acids and are expected to interfere with the interface between RBBP5 and the histones. In Drosophila, ubiquitous overexpression of human RBBP5 is lethal in the larval developmental stage. Loss of Rbbp5 leads to a reduction in brain size, and the human reference, p.T232I, or p.E296D variant transgenes fail to rescue loss of Rbbp5. Expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both p.T232I and p.E296D variants are loss-of-function alleles. ConclusionDe novo heterozygous variants in RBBP5 are associated with a syndromic neurodevelopmental disorder. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/578086v1_ufig1.gif" ALT="Figure 1"> O_LINKSMALLFIG WIDTH=200 HEIGHT=24 SRC="FIGDIR/small/578086v1_ufig1a.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@11337daorg.highwire.dtl.DTLVardef@b7f4d8org.highwire.dtl.DTLVardef@12bc283org.highwire.dtl.DTLVardef@1ef4e09_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

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↗

bioRxiv2024

KaMRaT: a C++ toolkit for k-mer count matrix dimension reduction

SummaryKaMRaT is a program for processing large k-mer count tables extracted from high throughput sequencing data. Major functions include scoring k-mers based on count statistics, merging overlapping k-mers into longer contigs and selecting k-mers based on their presence in certain samples. KaMRaT s main application is the reference-free analysis of multi-sample and multi-condition datasets from RNA-seq, as well as ChiP-seq or ribo-seq experiments. KaMRaT enables the identification of condition-specific or differential sequences, irrespective of any gene or transcript annotation. Implementation and availabilityKaMRaT is implemented in C++. Source code and documentation are available via https://github.com/Transipedia/KaMRaT. Container images are available via https://hub.docker.com/r/xuehl/kamrat.

bioinformatics↗

bioRxiv2023

Integrative genomics reveals the polygenic basis of seedlessness in grapevine

Seedlessness is a crucial quality trait in table grape (Vitis vinifera L.) breeding. However, the development of seeds involved intricate regulations, while the polygenic basis of seed abortion remains unclear. Here, we combine comparative genomics, population genetics, quantitative genetics, and integrative genomics to unravel the evolution and polygenic basis of seedlessness in grapes. We generated four haplotype-resolved telomere-to-telomere (T2T) genomes for two seedless grape cultivars, Thompson Seedless (TS, syn. Sultania) and Black Monukka (BM). Comparative genomics identified a [~]4.25 Mb hemizygous inversion on Chr10 specific in seedless cultivars, with seedless-associated genes VvTT16 and VvSUS2 located at breakpoints. Population genomic analyses of 548 grapevine accessions revealed two distinct clusters of seedless cultivars, tracing the origin of the seedlessness trait back to Sultania. Introgression, rather than convergent selection, shaped the evolutionary history of seedlessness in grape improvement. Genome-wide association study (GWAS) analysis identified 110 quantitative trait loci (QTLs) associated with 634 candidate genes, including novel candidate genes, such as three 11S GLOBULIN SEED STORAGE PROTEIN and two CYTOCHROME P450 genes, and well-known genes like VviAGL11. Integrative genomic analyses resulted in 339 core candidate genes categorized into 13 groups related to seed development. Machine learning based genomic selection achieved a remarkable 99% precision in predicting grapevine seedlessness. Our findings highlight the polygenic nature of seedless and provide novel candidate genes for molecular genetics and an effective prediction for seedlessness in grape genomic breeding.

genetics↗

bioRxiv2023

Powdery mildew infection induces a non-canonical route to storage lipid formation at the expense of host thylakoid lipids to fuel its spore production

Powdery mildews are obligate biotrophic fungi that manipulate plant metabolism to supply lipids, particularly during fungal asexual reproduction when fungal lipid demand is extensive. The mechanism for host response to fungal lipid demand has not been resolved. We found storage lipids, triacylglycerols (TAGs), increase by 3.5-fold in powdery mildew-infected tissue. In addition, lipid bodies, not observable in uninfected mature leaves, are present in both cytosol and chloroplasts at the infection site. This is concurrent with decreased thylakoid membrane lipids and thylakoid disassembly. Together, these findings indicate that the powdery mildew induces localized thylakoid membrane degradation to promote storage lipid formation. Genetic analyses show the canonical ER pathway for TAG synthesis does not support powdery mildew spore production. Instead, Arabidopsis DIACYLGLYCEROL ACYLTRANSFERASE 3 (DGAT3), shown to be chloroplast-localized and to be largely responsible for powdery mildew-induced chloroplast TAGs, promotes fungal asexual reproduction. Powdery mildew-induced leaf TAGs are enriched in thylakoid associated fatty acids, which are also present in the produced spores. This research provides new insights on obligate biotrophy and plant lipid metabolism plasticity and function. Furthermore, by understanding how photosynthetically active leaves can be converted into TAG producers, more sustainable and environmentally benign plant oil production could be facilitated.

plant biology↗

bioRxiv2023

Prognostic implications and biological roles of EMT-related lncRNAs in lung squamous cell carcinoma: an in-depth analysis utilizing a novel prognostic signature and classification system

BackgroundLung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer (NSCLC), a leading contributor to cancer-related mortality. Epithelial-mesenchymal transition (EMT)-associated genes have been implicated in poor survival and metastatic gene expression in LUSC. Long non-coding RNAs (lncRNAs) are known to facilitate tumor progression and metastasis via EMT regulation. However, the prognostic significance and biological functions of EMT-associated lncRNAs in LUSC remain to be elucidated. MethodsIn this study, we aimed to develop an EMT-related lncRNA prognostic signature (EMT-LPS) utilizing RNA transcription data from LUSC patients in The Cancer Genome Atlas (TCGA) database, along with corresponding clinical characteristics. Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and Cox regression were employed to validate and assess the model. Furthermore, we confirmed the independent prognostic value of key genes in EMT-LPS using Gene Expression Profiling Interactive Analysis (GEPIA). Additionally, we proposed a novel LUSC classification system based on EMT-related lncRNA expression patterns, evaluating the prognostic profile, tumor microenvironment, and immunotherapy sensitivity of each subtype. ResultsA prognostic signature comprising twelve genes was constructed, and patients were stratified into high and low-risk groups according to their risk scores. Cox regression analysis revealed that the risk score served as an independent prognostic factor. A nomogram was generated to predict LUSC patient survival rates. Distinct subtypes exhibited varying tumor purity, immunogenicity, and immunotherapy drug sensitivity. ConclusionsOur findings underscore the relevance of EMT-related lncRNAs in LUSC and their potential utility in guiding immunotherapy strategies. The EMT-LPS and novel LUSC typing scheme provide a new perspective for understanding the biological functions and prognostic role of EMT-related lncRNAs in LUSC.

bioinformatics↗

bioRxiv2023

Single-cell multi-omics map of human foetal blood in Down's Syndrome

Downs Syndrome (DS) predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood. To understand dysregulated hematopoiesis in DS, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human foetal liver and bone marrow samples from three disomic and 15 trisomic foetuses. We found that differences in gene expression in DS were both cell type- and environment-dependent. Furthermore, we found multiple lines of evidence that DS haematopoietic stem cells (HSCs) are "primed" to differentiate. We subsequently established a DS-specific map of enhancer-gene relationships in disomic and trisomic HSCs using 10X Multiome data. By integrating this map with genetic variants associated with blood cell variation, we discovered that trisomy restructured enhancer-gene maps to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Further, as DS mutations display a signature of oxidative stress, we validated both increased mitochondrial mass and oxidative stress in DS, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Altogether, our single- cell, multi-omic resource provides a high-resolution molecular map of foetal haematopoiesis in Downs Syndrome and indicates significant enhancer-gene restructuring giving rise to co- occurring haematological conditions.

genomics↗

bioRxiv2023

Development of an Accelerated Cellular Model for Alzheimer's Disease

Alzheimers Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. And progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated A{beta}42 to A{beta}40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening. Significance StatementAlzheimers Disease (AD) contributes to most dementia, while its mechanism is still under investigation. One of the challenges for studying AD is the model issue, including the genetic divergence of animals and human, and the rejuvenation of induced pluripotent stem cells (iPSCs). Progerin is a mutant lamin A found in the accelerated aging disease progeria. There are a lot of molecular similarities between Alzheimers Disease (AD) and progeria. Here, we developed an accelerated 2D/3D cell model system for AD by ectopically expressing progerin in a previously characterized AD cell model carrying familial AD (FAD) mutations. Our study showed that progerin addition could accelerate AD phenotypical progression, including tau phosphorylation and formation of {beta}-amyloid plaques.

cell biology↗

bioRxiv2023

A toxic ankyrin cysteine protease effector RipBH of brown rot triggered autophagy-associated cell death

Potato brown rot, caused by Ralstonia solanacearum, is one of the most destructive diseases of potatoes. The pathogen could hide in the tuber, leading to the rotting tubers. However, few mechanisms of pathogenesis in tubers caused by brown rot were reported. Here, we identified a highly virulent type III effector RipBH, which is not only required for the pathogenesis of potato brown rot but also displays strong cell toxicity in yeast and tobacco. We found RipBH is a novel structural cysteine protease with a large ankyrin repeat domain that contains 10 ankyrin repeats, we named it as an ankyrin cysteine protease. Biochemical analysis showed that all the ankyrin repeats are required for virulence, and the first five ankyrin repeats are indispensable for auto-cleavage site recognition. Further analysis showed that RipBH triggered autophagy-associated cell death. The ankyrin cysteine protease effector existed extensively in plant and animal pathogens suggesting the ankyrin cysteine protease effectors are functionally essential for pathogen pathogenesis. Our study enhances our understanding of this type of cysteine protease and illustrates the pathogenesis of cysteine protease in potato brown rot.

microbiology↗

bioRxiv2022

Deep Learning-based Feature Extraction with MRI Data in Neuroimaging Genetics for Alzheimer's Disease

The prognosis and treatment of the patients suffering from Alzheimers disease (AD) have been one of the most important and challenging problems over the last few decades. To better understand the mechanism of AD, it is of great interest to identify genetic variants associated with brain atrophy. Commonly in these analyses, neuroimaging features are extracted based on one of many possible brain atlases with FreeSurf and other popular softwares, which however may lose important information due to our incomplete knowledge about brain function embedded in these suboptimal atlases. To address the issue, we propose convolutional neural network (CNN) models applied to three-dimensional MRI data for the whole brain or multiple divided brain regions to perform completely data-driven and automatic feature extraction. These image-derived features are then used as endophenotypes in Genome-Wide Association Studies (GWAS) to identify associated genetic variants. When applied to the ADNI data, we identified several associated SNPs which have been previously shown to be related to several neurodegenerative/mental disorders such as AD, depression and schizophrenia. Code and supplementary materials are available at https://github.com/Dipnil07. The codes have been implemented using Python, R and Plink softwares.

bioinformatics↗

bioRxiv2022

Thermococci-to-Clostridia Pathway for the Evolution of the Bacteria Domain

With the identification of an archaeal Last Universal Common Ancestor phylogenetically related to Methanopyrus, the origin of Bacteria becomes a choice between independent emergence versus descent from Archaea. Recently, use of the similarity between paralogous valyl-tRNA synthetase (VARS) and isoleucyl-tRNA synthetase (IARS) as a measure of the ages of bacteria indicated that an Ancestral Bacterial Cluster centred at clostridial Mahella australiensis (Mau) were the oldest bacteria. Clostridial Thermincola potens (Tpo) also displayed an elevated similarity VARS-IARS bitscore. Overall, the high-bitscore bacteria dominated by Clostridia comprised a number of hydrogen producers. A search for archaea capable of hydrogen production that might be ancestral to the Bacteria domain yielded candidates led by Thermococci which, like Clostridia, form hydrogen through dark fermentation. A two-domain VARS tree based on Mahella, Thermincola, a broad spectrum of archaea together with both well known and newly reported species of Thermococci allocated these two Clostridia to a minor-Thermococcal division on the tree. The kinship between Thermoccoci and Clostridia suggested by this allocation was substantiated by conserved oligopeptide segments on their VARS sequences. It was therefore suggested that a Thermococci-to-Clostridia evolutionary pathway brought about the emergence of the Bacteria domain.

genomics↗

bioRxiv2022

Ralstonia solanacearum alters root developmental programs in auxin-dependent and independent manners

Microbial pathogens and other parasites can modify the development of their hosts, either as a target or a side effect of their virulence activities. The plant pathogenic bacterium Ralstonia solanacearum, causal agent of the devastating bacterial wilt disease, is a soil-borne microbe that invades host plants through their roots, and later proliferates in xylem vessels. In this work, we studied the early stages of R. solanacearum infection in the model plant Arabidopsis thaliana, using an in vitro infection system. In addition to the previously reported inhibition of primary root length and increase in root hair formation at the root tip, we observed an earlier xylem differentiation during R. solanacearum infection that occurs in a HrpG-dependent manner, suggesting that the pathogen actively promotes the development of the vascular system upon invasion of the root. Moreover, we found that the phytohormone auxin, of which the accumulation is promoted by the bacterial infection, is required for the R. solanacearum-triggered induction of root hair formation, but not earlier xylem differentiation. Altogether, our results shed light on the capacity of R. solanacearum to induce alterations of root developmental pathways and on the role of auxin in this process.

plant biology↗

bioRxiv2022

HiCHub: A Network-Based Approach to Identify Domains of Differential Interactions from 3D Genome Data

Chromatin architecture is important for gene regulation. Existing algorithms for the identification of interactions changes focus on loops between focal loci. Here we develop a network-based algorithm HiCHub to detect chromatin interaction changes at larger scales. It identifies clusters of genomic elements in physical proximity in one state that exhibit concurrent decreases in interaction among them in the opposite state. The hubs exhibit concordant changes in chromatin state and expression changes, supporting their biological significance. HiCHub works well with data of limited sequencing coverage and facilitates the integration of the one-dimensional epigenetic landscape onto the chromatin architecture. HiCHub provides an approach for finding extended architectural changes and contributes to the connection with transcriptional output. HiCHub is freely available at https://github.com/WeiqunPengLab/HiCHub.

bioinformatics↗

bioRxiv2022

Robust Inference of Bi-Directional Causal Relationships in Presence of Correlated Pleiotropy with GWAS Summary Data

To infer a causal relationship between two traits, several correlation-based causal direction (CD) methods have been proposed with the use of SNPs as instrumental variables (IVs) based on GWAS summary data for the two traits; however, none of the existing CD methods can deal with SNPs with correlated pleiotropy. Alternatively, reciprocal Mendelian randomization (MR) can be applied, which however may perform poorly in the presence of (unknown) invalid IVs, especially for bi-directional causal relationships. In this paper, first, we propose a CD method that performs better than existing methods regardless of the presence of correlated pleiotropy. Second, along with a simple but yet effective IV screening rule, we propose applying a closely related and state-of-the-art MR method in reciprocal MR, showing its almost identical performance to that of the new CD method when their model assumptions hold; however, if the modeling assumptions are violated, the new CD method is expected to better control type I errors. Notably bi-directional causal relationships impose some unique challenges beyond those for uni-directional ones, and thus requiring special treatments. For example, we point out for the first time several scenarios where a bi-directional relationship, but not a uni-directional one, can unexpectedly cause the violation of some weak modeling assumptions commonly required by many robust MR methods. Finally we applied the proposed methods to 12 risk factors and 4 common diseases, confirming mostly well-known uni-directional causal relationships, while identifying some novel and plausible bi-directional ones such as between BMI and T2D, and between BMI and CAD.

genetics↗

bioRxiv2022

Impaired Lef1 activation accelerates iPSC-derived keratinocytes differentiation in Progeria

Hutchinson-Gilford progeria syndrome (HGPS) is a detrimental premature aging disease caused by a point mutation in the human LMNA gene. This mutation results in the abnormal accumulation of a truncated pre-lamin A protein called progerin. Among the drastically accelerated signs of aging in HGPS patients, severe skin phenotypes such as alopecia and sclerotic skins always develop with the disease progression. Here, we study the HGPS molecular mechanisms focusing on early skin development by differentiating patient-derived induced pluripotent stem cells (iPSCs) to a keratinocyte lineage. Interestingly, HGPS iPSCs showed an accelerated commitment to the keratinocyte lineage than the normal control. To study potential signaling pathways that accelerated skin development in HGPS, we investigated the WNT pathway components during HGPS iPSCs-keratinocytes induction. Surprisingly, despite the unaffected {beta}-catenin activity, the expression of a critical WNT transcription factor LEF1 was diminished from an early stage in HGPS iPSCs-keratinocytes differentiation. Chromatin immunoprecipitation (ChIP) experiment further revealed strong bindings of LEF1 to the early-stage epithelial developmental markers K8 and K18 and that the LEF1 silencing by siRNA down-regulates the K8/K18 transcription. During the iPSCs-keratinocytes differentiation, correction of HGPS mutation by Adenine base editing (ABE), while in a partial level, rescued the phenotypes for accelerated keratinocyte lineage-commitment. ABE also reduced the cell death in HGPS iPSCs-derived keratinocytes. These findings brought new insight into the molecular basis and therapeutic application for the skin abnormalities in HGPS.

developmental biology↗