Biology subjects

Xu, J.

Publications and source records attributed to Xu, J..

64 records · Page 4Linked to original sources

bioRxiv2017

Finger recruitment patterns during mirror movements suggest two systems for hand recovery after stroke

Accumulating behavioural and neurophysiological evidence suggests that upper-limb control relies on contributions from both cortical and subcortical motor circuits, with cortical inputs providing fine-finger function and subcortical inputs providing the ability for gross movements, respectively. During recovery of function after stroke, the relative contributions from these pathways may shift. Here we propose that mirror movements that appear after stroke provide a non-invasive assay through which relative contributions from cortical and subcortical pathways towards hand recovery can be studied. We hypothesized that mirror movements, like hand function, are generated by summed contributions from cortical and subcortical pathways, and suggest that subcortical contributions should be characterized by a broad recruitment of fingers, while cortical contributions primarily recruit the homologous finger in the passive hand. In a longitudinal stroke recovery study (Xu et al., 2016), we quantified mirror movements and paretic hand function in 53 stroke patients in the year following unilateral stroke. Mirror movements in the non-paretic hand were exaggerated early after damage (week 2), with paretic finger presses broadly recruiting multiple fingers in the non-paretic hand. On average, however, mirroring in homologous fingers was 1.76 times larger than in non-homologous fingers. Over the year, mirroring in the non-paretic hand progressively normalized with a time-course that mimicked that for the fine-finger deficits in the paretic hand. In comparison, during non-paretic finger presses, the homologous component of mirroring in the paretic hand was reduced early after stroke (week 2) but progressively normalized. Altogether, we conclude that the pattern of mirror movements across homologous and non-homologous fingers reflect the summed contributions of both cortical and subcortical systems, and we discuss the implications of our results towards hand recovery after stroke.

neuroscience↗

bioRxiv2017

An Integrative Framework For Detecting Structural Variations In Cancer Genomes

Structural variants can contribute to oncogenesis through a variety of mechanisms, yet, despite their importance, the identification of structural variants in cancer genomes remains challenging. Here, we present an integrative framework for comprehensively identifying structural variation in cancer genomes. For the first time, we apply next-generation optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole genome sequencing to systematically detect SVs in a variety of cancer cells.\n\nUsing this approach, we identify and characterize structural variants in up to 29 commonly used normal and cancer cell lines. We find that each method has unique strengths in identifying different classes of structural variants and at different scales, suggesting that integrative approaches are likely the only way to comprehensively identify structural variants in the genome. Studying the impact of the structural variants in cancer cell lines, we identify widespread structural variation events affecting the functions of non-coding sequences in the genome, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel 3D chromatin structural domains.\n\nThese results underscore the importance of comprehensive structural variant identification and indicate that non-coding structural variation may be an underappreciated mutational process in cancer genomes.

genomics↗

bioRxiv2017

Replication Defective Viral Genomes Exploit A Cellular Pro-Survival Mechanism To Establish Viral Persistence

Replication defective viral genomes (DVGs) generated during virus replication are the primary triggers of antiviral immunity in many RNA virus infections. However, DVGs can also facilitate viral persistence. Why and how these two opposing functions of DVGs are achieved remain unknown. Here we report that during Sendai and respiratory syncytial virus infections DVGs selectively protect a subpopulation of cells from death and promote the establishment of persistent infections. We find that during Sendai virus infection this phenotype results from DVGs stimulating a MAVS-mediated TNF response that drives apoptosis of highly infected cells while extending the survival of cells enriched in DVGs. The pro-survival effect of TNF depends on the activity of the TNFR2/TRAF1 pathway that is regulated by MAVS signaling. These results identify TNF as a pivotal factor in determining cell fate during a viral infection and delineate a MAVS/TNFR2-mediated mechanism that drives the persistence of otherwise acute viruses.

microbiology↗

bioRxiv2017

Towards the human cellular microRNAome

microRNAs are short RNAs that serve as master regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell autonomously and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data has caused considerable confusion and comprehensive cell-level data does not yet exist. Here we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues. It identified both specific and ubiquitous patterns of expression that strongly correlate with adjacent super-enhancer activity. Analysis of unaligned RNA reads uncovered 207 unknown minor strand (passenger) microRNAs of known microRNA loci and 2,632 novel putative microRNA loci. Although cancer cell lines generally recapitulated the expression patterns of matched primary cells, their isomiR sequence families exhibited increased disorder suggesting Drosha and Dicer-dependent microRNA processing variability. Cell-specific patterns of microRNA expression were used to deconvolute variable cellular composition of adipose tissue samples highlighting one use of this cell-specific microRNA expression data. Characterization of cellular microRNA expression across a wide variety of cell types provides a new understanding of this critical regulatory RNA species.

genomics↗

bioRxiv2017

NLR1-V, a CC-NBS-LRR encoding gene, is a potential candidate gene of the wheat powdery mildew resistance gene Pm21

Wheat powdery mildew caused by Blumeria graminisb f. sp. tritici is one of the most destructive diseases all over the world. Pm21, transferred from the wild Haynaldia villosa to wheat, confers broad spectrum resistance throughout the whole stage, and this gene has been widely used in wheat production for more than 20 years. Cloning the candidate gene of Pm21 is the prerequisite for elucidating the resistance mechanism, and is a valuable attempt to clone the target genes from the evolutionarily distant wild species. In this study, an innovative approach, which combined cytogenetic stocks development, mutagenesis, RenSeq and PacBio, was tried successfully to clone an NBS-LRR type gene NLR1-V from the Pm21 locus. Firstly, a powdery mildew resistant cryptic alien introgression line HP33 involved very small 6VS segment was developed, and 6 independent susceptible mutants of T6VS {middle dot} 6AL was identified. Then, the transcriptome of H. villosa was obtained by NGS and the full-length NBS-LRR gene database was constructed by RenSeq-PacBio. In the following study, two expressed NLR genes were located to the Pm21 locus using the HP33 as the mapping material, and only NLR1-V showed polymorphism between the wild T6VS {middle dot} 6AL and its six mutants. The functional analysis indicated that silencing of NLR1-V could compromise the resistance of T6VS {middle dot} 6AL completely, and could also decrease the resistance of T6VS {middle dot} 6DL dramatically. Moreover, NLR1-V could recover the resistance of the susceptible mutant and increase the resistance in the susceptible wheat. The study implied that NLR1-V, a CC-NBS-LRR encoding gene, is a potential candidate gene of the powdery mildew resistance gene Pm21.

plant biology↗

bioRxiv2017

The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions

Recent advent of 3C-based technologies such as Hi-C and ChIA-PET provides us an opportunity to explore chromatin interactions and 3D genome organization in an unprecedented scale and resolution. However, it remains a challenge to visualize chromatin interaction data due to its size and complexity. Here, we introduce the 3D Genome Browser (http://3dgenome.org), which allows users to conveniently explore both publicly available and their own chromatin interaction data. Users can also seamlessly integrate other \"omics\" data sets, such as ChIP-Seq and RNA-Seq for the same genomic region, to gain a complete view of both regulatory landscape and 3D genome structure for any given gene. Finally, our browser provides multiple methods to link distal cis-regulatory elements with their potential target genes, including virtual 4C, ChIA-PET, Capture Hi-C and cross-cell-type correlation of proximal and distal DNA hypersensitive sites, and therefore represents a valuable resource for the study of gene regulation in mammalian genomes.

bioinformatics↗

bioRxiv2017

BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells (MSCs)

Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through activating specific downstream transcription factors. In this study, we used tooth root development as a model to investigate how the BMP signaling pathway regulates specific downstream transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-mediated transgenic animal model, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified transcription factors that are downstream of BMP signaling and are expressed in a spatially restricted pattern consistent with their potential involvement in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating the fate of MSCs during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development.\n\nSummary StatementBMP signaling activity is required for the lineage commitment of MSCs and transcription factors downstream of BMP signaling may determine distinct cellular identities within the dental mesenchyme.

developmental biology↗

bioRxiv2016

Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer’s disease

BackgroundGiven multiple studies of brain microRNA (miRNA) in relation to Alzheimers disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimers disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region.\n\nResultsWe report analyses of expression profiling of miRNA (n=700 subjects) and lincRNA (n=540 subjects) from the dorsolateral prefrontal cortex of individuals participating in two longitudinal cohort studies of aging. Evaluating well-established (miR-132, miR-129), we confirm their association with pathologic AD in our dataset, and then characterize their in disease role in terms of neuritic {beta}-amyloid plaques and neurofibrillary tangle pathology. Additionally, we identify one new miRNA (miR-99) and four lincRNA that are associated with these traits. Many other previously reported associations of microRNA with AD are associated with the confounders quantified in our longitudinal cohort. Finally, by performing analyses integrating both miRNA and RNA sequence data from the same individuals (525 samples), we characterize the impact of AD associated miRNA on human brain expression: we show that the effects of miR-132 and miR-129-5b converge on certain genes such as EP300 and find a role for miR200 and its target genes in AD using an integrated miRNA/mRNA analysis.\n\nConclusionsOverall, miRNAs play a modest role in human AD, but we observe robust evidence that a small number of miRNAs are responsible for specific alterations in the cortical transcriptome that are associated with AD.

neuroscience↗

bioRxiv2016

The emergence, evolution, and diversification of the miR390-TAS3-ARF pathway in land plants

In plants, miR390 directs the production of tasiRNAs from TRANS-ACTING SIRNA 3 (TAS3) transcripts to regulate AUXIN RESPONSIVE FACTOR (ARF) genes, transcription factors critical for auxin signaling; these tasiRNAs are known as tasiARFs. This pathway is highly conserved, with the TAS3 as the only one noncoding gene present almost ubiquitously in land plants. To understand the evolution of this miR390-TAS3-ARF pathway, we characterized homologs of these three genes from thousands of plant species, from bryophytes to angiosperms. Both miR390 and TAS3 are present and functional in liverworts, confirming their ancestral role to regulate ARFs in land plants. We found the lower-stem region of MIR390 genes, critical for accurate DCL1 (DICER-LIKE 1) processing, is conserved in sequence in seed plants. We propose a model for the transition of functional tasiRNA sequences in TAS3 genes occurred at the emergence of vascular plants, in which the two miR390 target sites of TAS3 genes showed distinct pairing patterns in different plant lineages. Based on the cleavability of miR390 target sites and the distance between target site and tasiARF we inferred a potential bidirectional processing mechanism exists for some TAS3 genes. We also demonstrated a tight mutual selection between tasiARF and its target genes, and characterized unusual aspects and diversity of regulatory components of this pathway. Taken together, these data illuminate the evolutionary path of the miR390-TAS3-ARF pathway in land plants, and demonstrate the significant variation that occurs in the production of phasiRNAs in plants, even in the functionally important and archetypal miR390-TAS3-ARF regulatory circuit.

evolutionary biology↗

bioRxiv2016

A sensitized mutagenesis screen in Factor V Leiden mice identifies novel thrombosis suppressor loci

Factor V Leiden (F5L) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized ENU mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for F5L (F5L/L) and haploinsufficient for tissue factor pathway inhibitor (Tfpi+/-). F8 deficiency enhanced survival of F5L/L Tfpi+/- mice, demonstrating that F5L/L Tfpi+/- lethality is genetically suppressible. ENU-mutagenized F5L/L males and F5L/+ Tfpi+/- females were crossed to generate 6,729 progeny, with 98 F5L/L Tfpi+/- offspring surviving until weaning. Sixteen lines exhibited transmission of a putative thrombosuppressor to subsequent generations, with these lines referred to as MF5L (Modifier of Factor 5 Leiden) 1-16. Linkage analysis in MF5L6 identified a chromosome 3 locus containing the tissue factor gene (F3). Though no ENU-induced F3 mutation was identified, haploinsufficiency for F3 (F3+/-) suppressed F5L/L Tfpi+/- lethality. Whole exome sequencing in MF5L12 identified an Actr2 gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of F5L/L Tfpi+/- lethality (p=1.7x10-6), suggesting that Actr2p.R258G is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent Actr2 knockin/knockout demonstrated that Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain of function mechanism of action for Actr2p.R258G. Our findings identify F8 and the Tfpi/F3 axis as key regulators in determining thrombosis balance in the setting of F5L and also suggest a novel role for Actr2 in this process.\n\nSignificance StatementVenous thromboembolism (VTE) is a common disease characterized by the formation of inappropriate blood clots. Inheritance of specific genetic variants, such as the Factor V Leiden polymorphism, increases VTE susceptibility. However, only ~10% of people inheriting Factor V Leiden develop VTE, suggesting the involvement of other genes that are currently unknown. By inducing random genetic mutations into mice with a genetic predisposition to VTE, we identified two genomic regions that reduce VTE susceptibility. The first includes the gene for blood coagulation Factor 3 and its role was confirmed by analyzing mice with an independent mutation in this gene. The second contains a mutation in the Actr2 gene. These findings identify critical genes for the regulation of blood clotting risk.

genetics↗