Biology subjects

Yu, L.

Publications and source records attributed to Yu, L..

17 recordsLinked to original sources

bioRxiv2018

Genome structure and evolution of Antirrhnum majus L.

Snapdragon (Antirrhinum majus L.), a member of Plantaginaceae, is an important model for plant genetics and molecular studies on plant growth and development, transposon biology and self-incompatibility. Here we report a high-quality genome assembly of A. majus cultivated JI7 (A. majus cv.JI7) of a 510 Mb with 37,714 annotated protein-coding genes. The scaffolds covering 97.12% of the assembled genome were anchored on 8 chromosomes. Comparative and evolutionary analyses revealed that Plantaginaceae and Solanaceae diverged from their most recent ancestor around 62 million years ago (MYA). We also revealed the genetic architectures associated with complex traits such as flower asymmetry and self-incompatibility including a unique TCP duplication around 46-49 MYA and a near complete{psi} S-locus of ca.2 Mb. The genome sequence obtained in this study not only provides the first genome sequenced from Plantaginaceae but also bring the popular plant model system of Antirrhinum into a genomic age.

genomics↗

bioRxiv2018

An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules

Covalent modifications of proteins with ubiquitin and ubiquitin-like molecules are instrumental to many biological processes. However, identifying the E3 ligase responsible for these modifications remains a major bottleneck in ubiquitin research. Here, we present an E2-thioester-driven identification (E2~dID) method for the targeted identification of substrates of specific E2 and E3 enzyme pairs. E2~dID exploits the central position of E2-conjugating enzymes in the ubiquitination cascade and provides in vitro generated biotinylated E2~ubiquitin thioester conjugates as the sole source for ubiquitination in extracto. This enables purification and mass spectrometry-based identification of modified proteins under stringent conditions independently of the biological source of the extract. We demonstrate the sensitivity and specificity of E2-dID by identifying and validating substrates of APC/C in human cells. Finally, we perform E2~dID with SUMO in S. cerevisiae, showing that this approach can be easily adapted to other ubiquitin-like modifiers and experimental models.

biochemistry↗

bioRxiv2018

Towards Decoding the Metabolic Plasticity in Cancer: Coupling of Gene Regulation and Metabolic Pathways

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities for better survival. Here, we establish a theoretical framework to model the coupling of gene regulation and metabolic pathways in cancer. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis respectively, with the activities of three metabolic pathways: glucose oxidation, glycolysis and fatty acid oxidation (FAO). Guided by the model, we develop metabolic pathway signatures to quantify the activities of glycolysis, FAO and the citric acid cycle of tumor samples by evaluating the expression levels of enzymes involved in corresponding processes. The association of AMPK/HIF-1 activity with metabolic pathway activity, predicted by the model and verified by analyzing the gene expression and metabolite abundance data of patient samples, is further validated by in vitro studies of aggressive triple negative breast cancer cell lines.

systems biology↗

bioRxiv2018

BAP1 deubiquitinase is a potent repressor of fetal hemoglobin biosynthesis

Human globin gene production transcriptionally \"switches\" from fetal to adult synthesis shortly after birth, and is controlled by macromolecular complexes that enhance or suppress transcription by cis-elements scattered throughout the locus. The DRED repressor is recruited to the {varepsilon}- and {gamma}-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA binding and epigenetic enzyme components (e.g. DNMT1 and LSD1) that elicit DRED function. We also describe a potent new regulator of {gamma}-globin repression: the deubiquitinase BAP1 is a component of the repressor complex whose activity maintains NCoR1 at sites in the {beta}-globin locus, and BAP1 inhibition in erythroid cells massively induces {gamma}-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate {gamma}-globin gene repression.

developmental biology↗

bioRxiv2018

Identification of key genes related to dexamethasone-resistance in acute lymphoblastic leukemia

Drug resistance is the main cause of poor chemotherapy response in acute leukemia. Despite the extensive use of dexamethasone(DEX) in the treatment of acute lymphoblastic leukemia for many years, the mechanisms of dexamethasone - resistance has not been fully understood. We choose GSE94302 from GEO database aiming to identify key genes that contribute to the DEX resistance in acute lymphoblastic leukemia. Differentially expressed gene(DEGs) are selected by using GEO2R tools. A total of 837 DEGs were picked out, including 472 up-regulated and 365 down-regulated DEGs. All the DEGs were underwent gene ontology(GO) analysis and Kyoto Encyclopedia of Gene and Genome(KEGG) pathway analysis. In addition, the DEGs-encoded protein-protein interaction (PPI) was screened by using Cytoscape and Search Tool for the Retrieval of Interacting Genes(STRING). Total 20 genes were found as key genes related to DEX resistance with high degree of connectivity, including CDK1, PCNA, CCNB1, MYC, KPNA2, AURKA, NDC80, HSPA4, KIF11, UBE2C, PIK3CG, CD44, CD19, STAT1, DDX41, LYN, BCR, CD48, JAK1 and ITGB1. They could be used as biomarkers to identify the DEX-resistant acute lymphoblastic leukemia.

bioinformatics↗

bioRxiv2018

Systematic Discovery of the Functional Impact of Somatic Genome Alterations in Individual Tumors through Tumor-specific Causal Inference

We report a tumor-specific causal inference (TCI) framework, which discovers causative somatic genome alterations (SGAs) through inferring causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and identified those SGAs that causally regulate the differentially expressed genes (DEGs) within each tumor. Overall, TCI identified 634 SGAs that cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both well-known and novel candidate drivers. By identifying major candidate drivers and revealing their functional impact in a tumor, TCI shed light on disease mechanisms of each tumor, providing useful information for advancing cancer biology and precision oncology.\n\nSignificance statementsCancer is mainly caused by SGAs. Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. TCI is a novel computational framework for discovering the causative SGAs and their impact on oncogenic processes, thus revealing tumor-specific disease mechanisms. This information can be used to guide precision oncology.

cancer biology↗

bioRxiv2018

Effect of visual cues in addition to moderate auditory cues on temporal coordination: A comparative study in humans and chimpanzees

Our previous studies reported that chimpanzees share an ability to produce spontaneous temporal coordination with humans (Yu & Tomonaga, 2015; 2016). However, it remains unclear how visual cues of an interacting partners movement influence on the emergence of tempo convergence. The current study conducted a comparative study in humans and chimpanzees under the same experimental setup as that used in Yu & Tomonaga (2016). Three conditions, including baseline, paired-invisible and paired-visible, were prepared. In the baseline condition, the participants produced the repetitive tapping movement alone. In contrast, in the other two paired conditions, the participants in a pair produced the tapping movement concurrently while facing a conspecific partner. However, in the paired-invisible condition, a visual barrier was placed in between the participants to control visual cues of an interacting partners movement. Moderate auditory cues, corresponding to each participants tapping movement, were presented throughout the conditions. Results showed that there are significant changes on the tapping tempo between baseline and the paired-invisible condition, whereas there are little changes between paired-invisible and paired-visible condition in both species. The current stepwise analysis across three conditions demonstrates that auditory cues were more influential than additive visual cues of an interacting partners movement on the tempo convergence in humans and chimpanzees.

animal behavior and cognition↗

bioRxiv2018

miR-21-5p and miR-30a-5p are identical in human and bovine, have similar isomiR distribution, and cannot be used to identify xenomiR uptake from cow milk

microRNAs (miRNAs) are often highly conserved across species, but species-specific sequences are known. In addition, miRNA \"isomiRs\" arise from the same precursor molecule but differ in post-processing length and modification, usually at the 3 end. A recently published feeding study reported the intriguing result that two bovine milk-specific miRNAs were taken up into human circulation after ingestion of bovine milk. Unfortunately, this interpretation is based on annotation errors in a public microRNA database. Reanalysis using databses including the MirGeneDB database reveals that the miRNAs in question, miR-21-5p and miR-30a-5p, arise from 100% identical 5 precursor sequences in human and bovine, and the putative bovine-specific isomiRs appear to be depleted, not enriched, in bovine milk. Thus, enrichment of these isomiRs in human blood is inconsistent with uptake of xenomiRs and likely betrays endogenous miRNA regulation in response to diet or technical artifact.

molecular biology↗

bioRxiv2018

A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed and belong to a very few prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death for >3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

cell biology↗

bioRxiv2017

Large protein complex production using the SmartBac System - Strategies and Applications

Recent revolution of cryo-electron microscopy has opened a new door to solve high-resolution structures of macromolecule complexes without crystallization while how to efficiently obtain homogenous macromolecule complex sample is therefore becoming a bottleneck. Here we report SmartBac, an easy and versatile system for constructing large-sized transfer plasmids used to generate recombinant baculoviruses that express large multiprotein complexes in insect cells. The SmartBac system integrates the univector plasmid-fusion system, Gibson assembly method and polyprotein strategy to construct the final transfer plasmids. The fluorescent proteins are designed to be co-expressed with recombinant proteins to monitor transfection and expression efficiencies. A scheme of screening an optimal tagged subunit for effective purification is provided. Six large multiprotein complexes including the human exocyst complex and dynactin complex were successfully expressed, suggesting a great potential of SmartBac for its wide application in the future structural biology study.

bioengineering↗

bioRxiv2017

A molecular network of the aging brain implicates INPPL1 and PLXNB1 in Alzheimer’s disease

The fact that only symptomatic therapies of small effect are available for Alzheimers disease (AD) today highlights the need for new therapeutic targets with which to prevent a major contributor to aging-related cognitive decline. Here, we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first identify the role of modules of coexpressed genes, and then confirm them in independent AD datasets. Then, we prioritize influential genes in AD-related modules and test our predictions in human model systems. We functionally validate two putative regulator genes in human astrocytes: INPPL1 and PLXNB1, whose activity in AD may be related to semaphorin signalling and type II diabetes, which have both been implicated in AD. This arc of network identification followed by statistical and experimental validation provides specific new targets for therapeutic development and illustrates a network approach to a complex disease.\n\nOne sentence summaryMolecular network analysis of RNA sequencing data from the aging human cortex identifies new Alzheimers and cognitive decline genes.

systems biology↗

bioRxiv2017

Genetic analysis of de novo variants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicates MYRF as a candidate gene

Congenital diaphragmatic hernia (CDH) is one of the most common and lethal birth defects. Previous studies using exome sequencing support a significant contribution of coding de novo variants in complex CDH cases with additional anomalies and likely gene-disrupting (LGD) variants in isolated CDH cases. To further investigate the genetic architecture of CDH, we performed exome or genome sequencing in 283 proband-parent trios. Combined with data from previous studies, we analyzed a total of 357 trios, including 148 complex and 209 isolated cases. Complex and isolated cases both have a significant burden of deleterious de novo coding variants (1.7~fold, p= 1.2x10-5 for complex, 1.5~fold, p= 9.0x10-5 for isolated). Strikingly, in isolated CDH, almost all of the burden is carried by female cases (2.1~fold, p=0.004 for likely gene disrupting and 1.8~fold, p= 0.0008 for damaging missense variants); whereas in complex CDH, the burden is similar in females and males. Additionally, de novo LGD variants in complex cases are mostly enriched in genes highly expressed in developing diaphragm, but distributed in genes with a broad range of expression levels in isolated cases. Finally, we identified a new candidate risk gene MYRF (4 de novo variants, p-value=2x10-10), a transcription factor intolerant of mutations. Patients with MYRF mutations have additional anomalies including congenital heart disease and genitourinary defects, likely representing a novel syndrome.

genomics↗

bioRxiv2017

Non-invasive detection of bladder cancer through the analysis of driver gene mutations and aneuploidy

Current non-invasive approaches for bladder cancer (BC) detection are suboptimal. We report the development of non-invasive molecular test for BC using DNA recovered from cells shed into urine. This \"UroSEEK\" test incorporates assays for mutations in 11 genes and copy number changes on 39 chromosome arms. We first evaluated 570 urine samples from patients at risk for BC (microscopic hematuria or dysuria). UroSEEK was positive in 83% of patients that developed BC, but in only 7% of patients who did not develop BC. Combined with cytology, 95% of patients that developed BC were positive. We then evaluated 322 urine samples from patients soon after their BCs had been surgically resected. UroSEEK detected abnormalities in 66% of the urine samples from these patients, sometimes up to 4 years prior to clinical evidence of residual neoplasia, while cytology was positive in only 25% of such urine samples. The advantages of UroSEEK over cytology were particularly evident in low-grade tumors, wherein cytology detected none while UroSEEK detected 67% of 49 cases. These results establish the foundation for a new, non-invasive approach to the detection of BC in patients at risk for initial or recurrent disease.

cancer biology↗

bioRxiv2017

Discordant association of the CREBRF rs373863828 minor allele with increased body mass index and protection from type 2 diabetes in Maori and Pacific (Polynesian) people living in New Zealand

Aim/HypothesesThe minor allele of CREBRF rs373863828 associates with increased body mass index (BMI) and reduced risk of type 2 diabetes (T2D) in the Samoan population of Samoa and American Samoa. Our aim was to test rs373863828 for association with BMI and odds of T2D, gout and chronic kidney disease (CKD) in M[a]ori and Pacific (Polynesian) people living in Aotearoa New Zealand in 2,286 adults.\n\nMethodsAssociation analyses were performed by linear and logistic regression with BMI, log-transformed BMI, waist circumference, T2D, gout and CKD. Analyses were adjusted for age, sex, the first four genome-wide principal components, and (when appropriate) BMI, waist circumference and T2D.\n\nResultsFor the minor allele of rs373863828 the effect size for log-transformed BMI was 0.038 (95% CI [0.022-0.055], P=4.8x10-6) and for T2D was OR=0.59 (95% CI [0.47-0.73], P=1.9x10-6). There was no evidence for association of genotype with variance in BMI (P=0.13). Nor was there evidence for association with serum urate ({beta}=0.012 mmol/L, Pc=0.10), gout (OR=1.00, P=0.98) or CKD (OR=0.91, P=0.59).\n\nConclusions/interpretationOur results replicated, with very similar effect sizes, association of the minor allele of rs373863828 with higher BMI but lower odds of T2D among New Zealand Polynesian adults, as in Samoan adults living in Samoa and American Samoa.

genetics↗

bioRxiv2017

The mechanism of transcription start site selection

During transcription initiation, RNA polymerase (RNAP) binds to promoter DNA, unwinds promoter DNA to form an RNAP-promoter open complex (RPo) containing a single-stranded \"transcription bubble,\" and selects a transcription start site (TSS). TSS selection occurs at different positions within the promoter region, depending on promoter sequence and initiating-substrate concentration. Variability in TSS selection has been proposed to involve DNA \"scrunching\" and \"antiscrunching,\" the hallmarks of which are: (i) forward and reverse movement of the RNAP leading edge, but not trailing edge, relative to DNA, and (ii) expansion and contraction of the transcription bubble. Here, using in vitro and in vivo protein-DNA photocrosslinking and single-molecule nanomanipulation, we show bacterial TSS selection exhibits both hallmarks of scrunching and anti-scrunching, and we define energetics of scrunching and anti-scrunching. The results establish the mechanism of TSS selection by bacterial RNAP and suggest a general mechanism for TSS selection by bacterial, archaeal, and eukaryotic RNAP.

molecular biology↗

bioRxiv2017

Brain xQTL Map: Integrating The Genetic Architecture Of The Human Brain Transcriptome And Epigenome

We perform quantitative trait locus (xQTL) analyses on a multi-omic dataset, comprising RNA sequence, DNA methylation, and histone acetylation ChIP sequence data from the dorsolateral prefrontal cortex of 411 older adult individuals. We identify SNPs that are significantly associated with gene expression, DNA methylation, and histone modification levels. Many SNPs influence more than one type of molecular feature, and epigenetic features are shown to mediate eQTLs in a number of (9%) such loci. We illustrate the utility of our new resource, xQTL Serve, in prioritizing the cell type most affected by an xQTL and in enhancing genome wide association studies (GWAS) as we report 18 additional CNS disease susceptibility loci after re-analyzing published studies.

bioinformatics↗

bioRxiv2017

Sub-minute phosphoregulation of cell-cycle systems during Plasmodium gamete formation revealed by a high-resolution time course

Malaria parasites are protists of the genus Plasmodium, whose transmission to mosquitoes is initiated by the production of gametes. Male gametogenesis is an extremely rapid process that is tightly controlled to produce eight flagellated microgametes from a single haploid gametocyte within 10 minutes after ingestion by a mosquito. Regulation of the cell cycle is poorly understood in divergent eukaryotes like Plasmodium, where the highly synchronous response of gametocytes to defined chemical and physical stimuli from the mosquito has proved to be a powerful model to identify specific phosphorylation events critical for cell-cycle progression. To reveal the wider network of phosphorylation signalling in a systematic and unbiased manner, we have measured a high-resolution time course of the phosphoproteome of P. berghei gametocytes during the first minute of gametogenesis. The data show an extremely broad response in which distinct cell-cycle events such as initiation of DNA replication and mitosis are rapidly induced and simultaneously regulated. We identify several protein kinases and phosphatases that are likely central in the gametogenesis signalling pathway and validate our analysis by investigating the phosphoproteomes of mutants in two of them, CDPK4 and SRPK1. We show these protein kinases to have distinct influences over the phosphorylation of similar downstream targets that are consistent with their distinct cellular functions, which is revealed by a detailed phenotypic analysis of an SRPK1 mutant. Together, the results show that key cell-cycle systems in Plasmodium undergo simultaneous and rapid phosphoregulation. We demonstrate how a highly resolved time-course of dynamic phosphorylation events can generate deep insights into the unusual cell biology of a divergent eukaryote, which serves as a model for an important group of human pathogens.

microbiology↗