Biology subjects

Lee, B.

Publications and source records attributed to Lee, B..

25 records · Page 2Linked to original sources

bioRxiv2017

Prometheus: omics portals for interkingdom comparative genomic analyses

Functional analyses of genes are crucial for unveiling biological responses, for genetic engineering, and for developing new medicines. However, functional analyses have largely been restricted to model organisms, representing a major hurdle for functional studies and industrial applications. To resolve this, comparative genome analyses can be used to provide clues to gene functions as well as their evolutionary history. To this end, we present Prometheus (http://prometheus.kobic.re.kr),web-based omics portal that contains more than 17,215 sequences from prokaryotic and eukaryotic genomes. This portal supports interkingdom comparative analyses via a domain architecture-based gene identification system, Gene Search, and users can easily and rapidly identify single or entire gene sets in specific pathways. Bioinformatics tools for further analyses are provided in Prometheus or through BioExpress, a cloud-based bioinformatics analysis platform. Prometheus suggests a new paradigm for comparative analyses with large amounts of genomic information.

bioinformatics↗

bioRxiv2017

Analysis of archaic human haplotypes suggest 5-hmC to act as epigenetic guide for meiotic point recombination

Meiotic \"point recombination\" refers to homologue recombination events affecting only individual SNPs. Driven mostly by gene conversion, it is common process that allows for a gradual adaptation and maturation of haplotypes during genetic evolution. In contrast to crossover recombination it is not tied to predetermined recombination sites and therefore assumed to occur largely randomly. Our analysis of archaic human haplotypes however revealed striking differences in the local point recombination rate. A linkage-study of 1.9 million SNPs defined by the sequence of denisovan hominids revealed low rates in introns and quiescent intergenic regions but high rates in splice sites, exons, 5- and 3-UTRs, and CpG islands. Correlations with ChIP-Seq tracks from ENCODE and other public sources identified a number of epigenetic modifications, that associated directly with these recombination events. A particularly tight association was observed for 5-hydroxymethylcytosine marks (5hmC). The mark was enriched in virtually all of the functional regions associated with elevated point recombination rates, including CpG islands and poised bivalent regions. As intermediate of oxidative demethylation, 5hmC is also a marker of recently opened gene loci. The data, thus, supports a model of guided evolution, in which point recombination is directed by 5hmC marks towards the functionally relevant regions.

evolutionary biology↗

bioRxiv2017

Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK-cell activity

Zika virus (ZIKV) has re-emerged in the population and caused unprecedented global outbreaks. Here, the transcriptomic consequences of ZIKV infection were studied systematically firstly in human peripheral blood CD14+ monocytes and monocyte-derived macrophages with high density RNA-sequencing. Analyses of the ZIKV genome revealed that the virus underwent genetic diversification and differential mRNA abundance was found in host cells during infection. Notably, there was a significant change in the cellular response with crosstalk between monocytes and natural killer (NK) cells as one of the highly identified pathway. Immune-phenotyping of peripheral blood from ZIKV-infected patients further confirmed the activation of NK cells during acute infection. ZIKV infection in peripheral blood cells isolated from healthy donors led to the induction of IFN{gamma} and CD107a -- two key markers of NK-cell function. Depletion of CD14+ monocytes from peripheral blood resulted in a reduction of these markers and reduced priming of NK cells during infection. This was complemented by the immunoproteomic changes observed. Mechanistically, ZIKV infection preferentially counterbalances monocyte and/or NK-cell activity, with implications for targeted cytokine immunotherapies.

immunology↗

bioRxiv2017

Anoctamin 9/TMEM16J is a Cation Channel Activated by cAMP/PKA Signal

Anoctamins are membrane proteins that consist of 10 homologs. ANO1 and ANO2 are anion channels activated by intracellular calcium that meditate numerous physiological functions. ANO6 is a scramblase that redistributes phospholipids across the cell membrane. However, the others are not well characterized. We found ANO9/TMEM16J is a cation channel activated by a cAMP-dependent PKA. Intracellular cAMP activated robust currents in whole-cells expressing ANO9 and inhibited by PKA blockers. A cholera toxin and purified PKA also activated ANO9. The cAMP-induced ANO9 currents were permeable to cations. The mutation of a possible phosphorylation site at Ser245 elicited a block of the cAMP-dependent activation. High levels of Ano9 transcripts were found in intestines. Human intestinal SW480 cells showed cAMP-dependent currents. We conclude that ANO9 is a cation channel activated by the cAMP/PKA pathway and could play a role in intestine function.

biophysics↗

bioRxiv2017

Systematic mapping of chromatin state landscapes during mouse development

Embryogenesis requires epigenetic information that allows each cell to respond appropriately to developmental cues. Histone modifications are core components of a cells epigenome, giving rise to chromatin states that modulate genome function. Here, we systematically profile histone modifications in a diverse panel of mouse tissues at 8 developmental stages from 10.5 days post conception until birth, performing a total of 1,128 ChIP-seq assays across 72 distinct tissue-stages. We combine these histone modification profiles into a unified set of chromatin state annotations, and track their activity across developmental time and space. Through integrative analysis we identify dynamic enhancers, reveal key transcriptional regulators, and characterize the role of chromatin-based repression in developmental gene regulation. We also leverage these data to link enhancers to putative target genes, revealing connections between coding and non-coding sequence variation in disease etiology. Our study provides a compendium of resources for biomedical researchers, and achieves the most comprehensive view of embryonic chromatin states to date.

genomics↗

bioRxiv2017

Gestational Age At Birth And Risk Of Intellectual Disability Without A Common Genetic Cause: Findings From The Stockholm Youth Cohort

BackgroundPreterm birth is linked to intellectual disability and there is evidence to suggest post-term birth may also incur risk. However, these associations have not yet been investigated in the absence of common genetic causes of intellectual disability (where risk associated with late delivery may be preventable) or with methods allowing stronger causal inference from non-experimental data. We aimed to examine risk of intellectual disability without a common genetic cause across the entire range of gestation, using a matched-sibling design to account for unmeasured confounding by shared familial factors.\n\nMethods and FindingsWe conducted a population-based retrospective study using data from the Stockholm Youth Cohort (n=499,621) and examined associations in a nested cohort of matched siblings (n=8,034). Children born at non-optimal gestational duration (before/after 40 weeks 3 days) were at greater risk of intellectual disability. Risk was greatest among those born extremely early (adjusted OR24 weeks=14.54 [95% CI 11.46-18.44]), lessening with advancing gestational age toward term (aOR32 weeks=3.59 [3.22-4.01]; aOR37 weeks=1.50 [1.38-1.63]); aOR38 weeks=1.26 [1.16-1.37]; aOR39 weeks=1.10 [1.04-1.17]) and increasing with advancing gestational age post-term (aOR42 weeks=1.16 [1.08-1.25]; aOR42 weeks=1.41 [1.21-1.64]; aOR44 weeks=1.71 [1.34-2.18]; aOR45 weeks=2.07 [1.47-2.92]). Associations persisted in a nested cohort of matched outcome-discordant siblings suggesting they were robust against confounding from shared genetic or environmental traits, although there may have been residual confounding by unobserved non-shared characteristics. Risk of intellectual disability was greatest among children showing evidence of fetal growth restriction, especially when birth occurred before or after term.\n\nConclusionsBirth at non-optimal gestational duration may be linked causally with greater risk of intellectual disability. The mechanisms underlying these associations need to be elucidated as they will be relevant to clinical practice concerning elective delivery within the term period and the mitigation of risk in children who are born post-term.

epidemiology↗

bioRxiv2016

Ras/ERK-signalling promotes tRNA synthesis and growth via the RNA polymerase III repressor Maf1 in Drosophila

The small G-protein Ras is a conserved regulator of cell and tissue growth. These effects of Ras are mediated largely through activation of a canonical RAF-MEK-ERK kinase cascade. An important challenge is to identify how this Ras/ERK pathway alters cellular metabolism to drive growth. Here we report on stimulation of RNA polymerase III (Pol III)-mediated tRNA synthesis as a growth effector of Ras/ERK signalling in Drosophila. We find that activation of Ras/ERK signalling promotes tRNA synthesis both in vivo and in cultured Drosophila S2 cells. We also show that Pol III function is required for Ras/ERK signalling to drive proliferation in both epithelial and stem cells in Drosophila tissues. We find that the transcription factor Myc is required but not sufficient for Ras-mediated stimulation of tRNA synthesis. Instead we show that the main way that Ras promotes Pol III function and tRNA synthesis is by inhibiting the nuclear localization and function of the Pol III repressor Maf1. We propose that inhibition of Maf1 and stimulation of tRNA synthesis is one way by which Ras signalling enhances protein synthesis to promote cell and tissue growth.

developmental biology↗