Biology subjects

Huang, H.

Publications and source records attributed to Huang, H..

At least 19 recordsLinked to original sources

bioRxiv2018

Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

BackgroundGlomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets.\n\nMethodsRenal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.\n\nResultsIn the discovery cohort, 10-25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60-77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFR-based outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (p<0.001), a JAK-STAT biomarker, predictors of CKD progression, interstitial fibrosis (r=0.41, p<0.001), and urinary EGF (r=-0.51, p<0.001).\n\nConclusionAAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.

systems biology↗

bioRxiv2018

A familial case of Syndactyly type IV due to a novel duplication of ~222.23 kb covering exons 2-17 of the LMBR1 gene: a case report

Syndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant Syndactyly type IV (SD4) is a very rare form of syndactyly, occurring as a result of heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. The SD4 is characterized by complete cutaneous syndactyly of all fingers, cup-shaped hands due to flexion of the fingers and accompanied by polydactyly. Here, we firstly reported a big Chinese family, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). Genetically, we identified a novel duplication of [~]222.23 kb covering exons 2-17 of the LMBR1 gene in this family by next generation sequencing. This case expands our new clinical understanding of SD4 phenotype.

genetics↗

bioRxiv2018

Diagnostic Whole Exome Sequencing in Patients with Short Stature

Short stature is among the most common reasons for children being referred to the pediatric endocrinology clinics. The cause of short stature is broad, in which genetic factors play a substantial role, especially in primary growth disorders. However, identifying the molecular causes for short stature remains as a challenge because of the high heterogeneity of the phenotypes. Here, whole exome sequencing (WES) was used to identify the genetic causes of short stature with unknown etiology for 20 patients aged from 1 to 16 years old. The genetic causes of short stature were identified in 9 of the 20 patients, corresponding to a molecular diagnostic rate of 45%. Notably, in 2 of the 9 patients identified with genetic causes, the diagnosed diseases based on WES are different from the original clinical diagnosis. Our results highlight the clinical utility of WES in the diagnosis of rare, high heterogeneity disorders.

genetics↗

bioRxiv2018

Network analysis of lymphocyte nucleus staining image

Background: A complex network has been studied and applied in various disciplines. As network analysis and image processing are based on matrices, this research analysed the changes in the chromatin image of lymphocyte nuclei in peripheral blood of humans using a network motif and static features (static parameters), so as to complete image classification with network method.\n\nMethods: Image processing technology was used to establish a chromatin image network of a cell nucleus; Network analysis tool Pajek was used to display the special motif of an isolated structural hole with different symmetric line values; afterwards, the frequency of occurrence of this structural hole in patients with nasopharyngeal carcinoma and AIDS, and healthy people was computed. Then by applying the network static features as variables, the chromatin images of stained lymphocytes from the three groups of people were classified and recognised by using an extreme learning machine (ELM).\n\nResults: The frequency of occurrence of the isolated structural hole with different symmetric line values was adopted to distinguish the structures of the chromatins of peripheral blood lymphocytes in patients with nasopharyngeal carcinoma and AIDS, and healthy people. Similarly, The static features of the chromatin image network of a cell nucleus were applied to classify and recognise the morphological and structural changes in chromatins for peripheral blood lymphocytes in the three groups of people.\n\nConclusion: The surface chemical and physical characteristics, as well as the polymerisation link status of biomacromolecules such as DNA, RNA, and protein in the lymphocyte nucleus change under certain pathological conditions. The change influences the combination of small molecular staining materials and any associated biomacromolecules. Therefore, various macroscopic and microscopic changes were found in the chromatin images of the cell nucleus. The microscopic changes include the variations of the extent of staining of chromatin in the nuclei, coarseness and direction of the texture therein, the size of stained conglomerations, etc. These changes contribute to the differences in chromatin image networks among the same type of cells across the three groups. Based on this, the model can be used to classify and reorganise certain diseases. The results prove that using complex network to analyse the chromatin structure of a cell nucleus is of significance.

bioinformatics↗

bioRxiv2018

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

The sarcomatoid variant of urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment of TP53, RB1, and PIK3CA mutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

genomics↗

bioRxiv2018

AICM: A Genuine Framework for Correcting Inconsistency Between Large Pharmacogenomics Datasets

The inconsistency of open pharmacogenomics datasets produced by different studies limits the usage of pharmacogenomics in biomarker discovery. Investigation of multiple pharmacogenomics datasets confirmed that the pairwise sensitivity data correlation between drugs, or rows, across different studies (drug-wise) is relatively low, while the pairwise sensitivity data correlation between cell-lines, or columns, across different studies (cell-wise) is considerably strong. This common interesting observation across multiple pharmacogenomics datasets suggests the existence of subtle consistency among the different studies (i.e., strong cell-wise correlation). However, significant noises are also shown (i.e., weak drug-wise correlation) and have prevented researchers from comfortably using the data directly. Motivated by this observation, we propose a novel framework for addressing the inconsistency between large-scale pharmacogenomics data sets. Our method can significantly boost the drug-wise correlation and can be easily applied to re-summarized and normalized datasets proposed by others. We also investigate our algorithm based on many different criteria to demonstrate that the corrected datasets are not only consistent, but also biologically meaningful. Eventually, we propose to extend our main algorithm into a framework, so that in the future when more data-sets become publicly available, our framework can hopefully offer a \"ground-truth\" guidance for references.

bioinformatics↗

bioRxiv2018

Urinary protein changes in the early phase of smoking-induced Chronic Obstructive Pulmonary Disease in a rat model

Chronic obstructive pulmonary disease (COPD) is a group of severe respiratory diseases. Identifying COPD through early urinary biomarkers by proteomics technology may help to reduce the mortality rate of the disease, improve the quality of life of patients and reduce the burden on society. Urine samples from a COPD rat model induced by smoking were taken at week 2, week 4 and week 8. By LC-MS/MS, 15 differential proteins with human orthologs were identified. After smoking for 2 weeks when there were no significant pathological changes, 8 differential proteins were identified: 2 proteins had been reported to be markers of COPD, while 4 proteins were associated with COPD. After smoking for 4 weeks, which is when slight pathological changes were observed, 7 differential proteins were identified: 3 of them were reported to be associated with COPD, while 1 protein had been reported to be a marker of COPD. After smoking for 8 weeks, there were significant pathological changes: 5 differential proteins were identified, 3 of which were reported to be associated with COPD. The results of this study suggest that differential urinary proteins may provide important clues for the early diagnosis of COPD.

biochemistry↗

bioRxiv2018

De novo transcriptomic characterization of Betta splendens for identifying sex-biased genes potentially involved in aggressive behavior modulation and EST-SSR maker development

Betta splendens is not only a commercially important labyrinth fish but also a nice research model for understanding the biological underpinnings of aggressive behavior. However, the shortage of basic genetic resource severely inhibits investigations on the molecular mechanism in sexual dimorphism of aggressive behavior typicality, which are essential for further behavior-related studies. There is a lack of knowledge regarding the functional genes involved in aggression expression. The scarce marker resource also impedes research progress of population genetics and genomics. In order to enrich genetic data and sequence resources, transcriptomic analysis was conducted for mature B. splendens using a multiple-tissues mixing strategy. A total of 105,505,486 clean reads were obtained and by de novo assembly, 69,836 unigenes were generated. Of which, 35,751 unigenes were annotated in at least one of queried databases. The differential expression analysis resulted in 17,683 transcripts differentially expressed between males and females. Plentiful sex-biased genes involved in aggression exhibition were identified via a screening from Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, such as htr, drd, gabr, cyp11a1, cyp17a1, hsd17b3, dax1, sf-1, hsd17b7, gsdf1 and fem1c. These putative genes would make good starting points for profound mechanical exploration on aggressive behavioral regulation. Moreover, 12,751 simple sequence repeats were detected from 9,617 unigenes for marker development. Nineteen of the 100 randomly selected primer pairs were demonstrated to be polymorphic. The large amount of transcript sequences will considerably increase available genomic information for gene mining and function analysis, and contribute valuable microsatellite marker resources to in-depth studies on molecular genetics and genomics in the future.

zoology↗

bioRxiv2018

Zebrafish hhex null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1

The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder and pancreatic duct. Haematopoietically-expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD, however, the molecular mechanism remains elusive. Here we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty-acid-binding-protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 were expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 restored the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis shows that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b and Pdx1 form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

developmental biology↗

bioRxiv2018

Proteomics reveals ablation of placental growth factor inhibits the insulin resistance pathways in diabetic mouse retina

The underlying molecular mechanisms that placental growth factor (PlGF) mediates the early complications at non-proliferative diabetic retinopathy (DR) remain largely elusive. The objective of this study is to characterize expression profile due to PlGF ablation in the retina of diabetic mice. The quantitative label-free proteomics was carried out on retinal tissues collected from mouse strains (Akita; PlGF-/- and Akita.PlGF-/-). We have identified 3176 total proteins, and 107 were significantly different between the experimental groups, followed by gene ontology, functional pathways, and protein-protein network interaction analysis. Gnb1, Gnb2, Gnb4, Gnai2, Gnao1, Snap25, Stxbp1, Vamp2 and Gngt1 proteins are involved in insulin resistance pathways, which are down-regulated in PlGF ablation in Akita diabetics (Akita.PlGF-/- vs. Akita), up-regulation in Akita vs. C57, PlGF-/- vs. C57. Prdx6, Prdx5 (up-regulation) are known of antioxidant activity; Map2 is involved in neural protection pathways which are up-regulated in Akita.PlGF-/- vs. Akita. Our results suggest that inhibition of insulin resistance pathway and the enhancement of antioxidant defence and neural function may represent the potential mechanisms of anti-PlGF compounds in the treatment of DR.

molecular biology↗

bioRxiv2018

Visualizing APP trafficking and processing reveals its association with neuronal membrane cholesterol

The amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimers disease (AD). However, APP distribution across different subcellular membrane compartments and its function in neurons remains unclear. We generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain and used it to measure APPs distribution, subcellular trafficking and cleavage in live neurons. This reporter, closely resembling endogenous APP, revealed only a limited correlation between synaptic activities and APP trafficking. However, the synaptic surface distribution of APP was inversely correlated to membrane cholesterol levels, a phenomenon that involves APPs cholesterol-binding site. Mutations within this site not only altered surface APP and cholesterol levels in a dominant negative manner, but also increased synaptic vulnerability to moderate membrane cholesterol reduction. Our results reveal reciprocal modulation of APP and membrane cholesterol levels at synaptic boutons.

neuroscience↗

bioRxiv2018

Urine proteome changes in a TNBS-induced colitis rat model

Urine is an important resource for biomarker research. Without homeostasis, urine accumulates markers of all the changes in the body. Urine proteins reflect not only renal diseases but also changes in other organs in the body. However, urine has rarely been used to reflect inflammatory bowel disease. In the present study, a trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model was used to mimic the human inflammatory bowel disease Crohns disease (CD). Urine samples from a control group (n=3), a TNBS 2-day group (n=3) and a TNBS 7-day group (n=3) were analyzed for candidate biomarker discovery by label-free and TMT-labeled proteomic quantitative methods. Seventy-seven urinary proteins were significantly changed in the colitis rats compared with that in the controls. These proteins were further validated by parallel reaction monitoring (PRM) targeted proteomic quantitative methods. Urine samples from the control group (n=8), the TNBS 2-day group (n=11) and the TNBS 7-day group (n=11) were analyzed by PRM. This led to the identification of 9 significantly differential expressed urinary proteins: CAH1, G3P, MMP-8, MANBA, NGAL, RNS1G, SLC31, S6A18, and TMM27. Based on the human protein tissue atlas, CAH1, RNS1G and SLC31 are highly enriched in the gastrointestinal tract. Among the 9 PRM-validated proteins, CAH1, MMP-8 and NGAL were previously reported as IBD-associated proteins (all exhibiting consistent trends with our observation), whereas the others are newly discovered by this study. Our results provide valuable clues for future study of urine biomarker of inflammatory bowel disease and Crohns disease.

molecular biology↗

bioRxiv2018

The effector of Hippo signaling, Taz, is required for formation of the micropyle and fertilization in zebrafish

The mechanisms that ensure fertilization of eggs by a single sperm are not fully understood. In all teleosts, a channel called the micropyle is the only route of entry for sperm to enter and fertilize the egg. The micropyle forms by penetration of the developing vitelline envelope by a single specialized follicle cell, the micropylar cell, which subsequently degenerates. The mechanisms underlying micropylar cell specification and micropyle formation are poorly understood. Here, we show that an effector of the Hippo signaling pathway, the Transcriptional co-activator with a PDZ-binding domain (Taz), plays crucial roles in micropyle formation and fertilization in zebrafish. Genome editing mutants affecting taz can grow to adults, however, eggs from homozygous taz females are not fertilized even though oocytes in mutant females are histologically normal with intact animal-vegetal polarity, complete meiosis and proper ovulation. However, taz mutant eggs have no micropyle. We show that Taz protein is specifically enriched from mid-oogenesis onwards in two follicle cells located at the animal pole of the oocyte, and co-localizes with the actin and tubulin cytoskeleton. Taz protein and micropylar cell are not detected in taz mutant ovaries. Our work identifies a novel role for the Hippo/Taz pathway in micropylar cell specification in zebrafish, and uncovers the molecular basis of micropyle formation in teleosts.

developmental biology↗

bioRxiv2018

Oscillatory cortical forces promote three dimensional cell intercalations that shape the mandibular arch

Multiple vertebrate embryonic structures such as organ primordia are composed of a volume of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show 3D mesenchymal cell intercalations, rather than cell divisions and biophysical tissue properties, are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor, we show that cortical force oscillations promote these intercalations. Genetic loss and gain of function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity with cytoskeletal oscillation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin bias and cytosolic calcium transients, respectively, to ensure appropriate tissue form during growth. Our data support oriented 3D cell neighbour exchange as a conserved mechanism driving volumetric morphogenesis.

developmental biology↗

bioRxiv2018

Local adaptation and maladaptation during the worldwide range expansion of a self-fertilizing plant

Species having experienced rapid range expansion represent unique opportunities to evaluate the dynamics of adaptation during colonization of new environments. We investigated the consequences of range expansion on local adaptation of a successful worldwide colonizer, the shepherds purse Capsella bursa-pastoris. This species is an annual weed that originated recently in Eurasia and has now broadly colonized both temperate and subtropical areas. We assessed the performance, genetic diversity, and phenology of field-collected accessions belonging to three distinct genetic clusters of decreasing age (Middle East, Europe and Asia) in three common gardens in Europe, Asia and North America. To understand the genetic basis of local adaptation in this species, we also tested for correlation between SNP allele frequencies and environmental factors in Europe and Asia. Overall, we showed that patterns of local adaptation depended on population history: some older populations were weakly adapted to local conditions while those closer to the front of the colonization wave, far from the origin of the species, were maladapted whatever the common gardens. Altogether, our results have important consequences for the understanding of the evolution and adaptation of self-fertilizing plant during range expansion.

evolutionary biology↗

bioRxiv2018

EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

With the unfolding of more and more cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target different mutants rather than develop strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation sequencing (RIP-seq) we identified EZH2 as a p53 mRNA-binding protein. EZH2 bound to the internal ribosome entry site (IRES) in the 5 untranslated region (5UTR) of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing p53 GOF mutant protein level. EZH2 overexpression associated with the worse outcome only in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.

cancer biology↗

bioRxiv2018

Large-Scale Genome-Wide Meta Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed with different criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease indicate shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. Only one locus differed in its association by diagnostic criteria, otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or Rotterdam criteria across common variants at 13 loci.

genetics↗

bioRxiv2017

The ecological genetics of Pseudomonas syringae residing on the kiwifruit leaf surface

Interactions between commensal microbes and invading pathogens are understudied, despite their likely effects on pathogen population structure and infection processes. We describe the population structure and genetic diversity of a broad range of co-occurring Pseudomonas syringae isolated from infected and uninfected kiwifruit during an outbreak of bleeding canker disease caused by P. syringae pv. actinidiae (Psa) in New Zealand. Overall population structure was clonal and affected by ecological factors including infection status and cultivar. Most isolates are members of a new clade in phylogroup 3 (PG3a), also present on kiwifruit leaves in China and Japan. Stability of the polymorphism between pathogenic Psa and commensal P. syringae PG3a isolated from the same leaf was tested using reciprocal invasion from rare assays in vitro and in planta. P. syringae G33C (PG3a) inhibited Psa NZ54, while the presence of Psa NZ54 enhanced the growth of P. syringae G33C. This effect could not be attributed to virulence activity encoded by the Type 3 secretion system of Psa. Together our data contribute toward the development of an ecological perspective on the genetic structure of pathogen populations.\n\nORIGINALITY-SIGNIFICANT STATEMENTBacterial pathogen populations are often studied with little consideration of co-occurring microbes and yet interactions between pathogens and commensals can affect both population structure and disease progression. A fine-scale sampling of commensals present on kiwifruit leaves during an outbreak of bleeding canker disease caused by P. syringae pv. actinidiae reveals a clonal population structure. A new clade of non-pathogenic P. syringae (PG3a) appears to be associated with kiwifruit on a global scale. The presence of PG3a on kiwifruit has significant effects on the outcome of infection by P. syringae pv. actinidiae. This emphasises the value of studying the effect of co-occurring bacteria on pathogen-plant interactions.

microbiology↗