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MicroRNA duplication accelerates the recruitment of new targets during vertebrate evolution

Mar 14，2018

The repertoire of miRNAs has considerably expanded during metazoan evolution, and duplication is an important mechanism for generating new functional miRNAs. However, relatively little is known about the functional divergence between paralogous miRNAs and the possible co-evolution between duplicated miRNAs and the genomic contexts. By systematically examining small RNA expression profiles across various human tissues and interrogating the publicly available miRNA:mRNA pairing chimeras, we found that changes in expression patterns and targeting preferences are widespread for duplicated miRNAs in vertebrates. Both the empirical interactions and target predictions suggest evolutionarily conserved homo-seed duplicated miRNAs pair significantly higher numbers of target sites compared to the single-copy miRNAs. Our birth-and-death evolutionary analysis revealed that the new target sites of miRNAs experienced frequent gains and losses during function development. Our results suggest that a newly emerged target site has a higher probability to be functional and maintained by natural selection if it is paired to a seed shared by multiple paralogous miRNAs than being paired to a single-copy miRNA. We experimentally verified the divergence in target repression between two paralogous miRNAs by transfecting let-7a and let-7b mimics into kidney-derived cell lines of four mammalian species and measuring the resulting transcriptome alterations by extensive high-throughput sequencing. Our results also suggest that the gains and losses of let-7 target sites might be associated with the evolution of repressiveness of let-7 across mammalian species.

A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy

Mar 07，2018

This study identifies the ubiquitin-editing enzyme A20 as a key factor in mediating cancer cell resistance to DNA-damaging therapy, with implications for blocking its function to leverage the efficacy of chemotherapy and radiotherapy.

Structural Basis for Draxin-Modulated Axon Guidance and Fasciculation by Netrin-1 through DCC

Mar 02，2018

•Crystal structure of cysteine knot domain of Draxin in complex with DCC •Crystal structure of Netrin-1 in complex with a Draxin fragment •Netrin-1 contains a competing binding site for DCC and Draxin on the EGF-3 domain •Draxin tethers Netrin-1 and DCC together to promote fasciculation

Nature vs. nurture in human sociality: multi-level genomic analyses of social conformity

Mar 01，2018

Social conformity is fundamental to human societies and has been studied for more than six decades, but our understanding of its mechanisms remains limited. Individual differences in conformity have been attributed to social and cultural environmental influences, but not to genes. Here we demonstrate a genetic contribution to conformity after analyzing 1,140 twins and single-nucleotide polymorphism (SNP)-based studies of 2,130 young adults. A two-step genome-wide association study (GWAS) revealed replicable associations in 9 genomic loci, and a meta-analysis of three GWAS with a sample size of ~2,600 further confirmed one locus, corresponding to the NAV3 (Neuron Navigator 3) gene which encodes a protein important for axon outgrowth and guidance. Further multi-level (haplotype, gene, pathway) GWAS strongly associated genes including NAV3, PTPRD (protein tyrosine phosphatase receptor type D), ARL10 (ADP ribosylation factor-like GTPase 10), and CTNND2 (catenin delta 2), with conformity. Magnetic resonance imaging of 64 subjects shows correlation of activation or structural features of brain regions with the SNPs of these genes, supporting their functional significance. Our results suggest potential moderate genetic influence on conformity, implicate several specific genetic elements in conformity and will facilitate further research on cellular and molecular mechanisms underlying human conformity.

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Feb 28，2018

Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3′ untranslated regions (3′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3′ UTRs and reduced gene expression. Genes that harbor longer 3′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core “AGAA” motif located in the alternative 3′ UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.

Mutual Information and Information Gating in Synfire Chains

Feb 06，2018

Coherent neuronal activity is believed to underlie the transfer and processing of information in the brain. Coherent activity in the form of synchronous firing and oscillations has been measured in many brain regions and has been correlated with enhanced feature processing and other sensory and cognitive functions. In the theoretical context, synfire chains and the transfer of transient activity packets in feedforward networks have been appealed to in order to describe coherent spiking and information transfer. Recently, it has been demonstrated that the classical synfire chain architecture, with the addition of suitably timed gating currents, can support the graded transfer of mean firing rates in feedforward networks (called synfire-gated synfire chains—SGSCs). Here we study information propagation in SGSCs by examining mutual information as a function of layer number in a feedforward network. We explore the effects of gating and noise on information transfer in synfire chains and demonstrate that asymptotically, two main regions exist in parameter space where information may be propagated and its propagation is controlled by pulse-gating: a large region where binary codes may be propagated, and a smaller region near a cusp in parameter space that supports graded propagation across many layers.

Effects of the Qinghai-Tibet Railway on the Landscape Genetics of the Endangered Przewalski’s Gazelle (Procapra przewalskii)

Dec 24，2017

The Przewalski’s gazelle (Procapra przewalskii) is one of the most endangered ungulates in the world, with fewer than 2,000 individuals surviving in nine habitat fragments on the Qinghai-Tibet Plateau and isolated by human settlements and infrastructure. In particular, the Qinghai-Tibet railway, which crosses the largest part of the gazelle’s distribution, remains a major concern because of its potential to intensify landscape genetic differentiation. Here, using mtDNA sequencing and microsatellite genotyping to analyze 275 Przewalski’s gazelle samples collected throughout the range, we observed low level of genetic diversity (mtDNA π = 0.0033) and strong phylogeographic structure. Overall, the nine patches of gazelles can be further clustered into five populations, with a strong division between the eastern vs. western side of Qinghai Lake. Our study provides the first evidence of the genetic divergence between the Haergai North and Haergai South gazelle populations, corresponding to the recent construction of a wired enclosure along the Qinghai-Tibet railway less than ten years ago, an equivalent of five generations. Well-designed wildlife corridors across the railway along with long-term monitoring of the anthropogenic effects are therefore recommended to alleviate further habitat fragmentation and loss of genetic diversity in Przewalski’s gazelle.

Single-cell DNA methylome sequencing of human preimplantation embryos

Dec 19，2017

DNA methylation is a crucial layer of epigenetic regulation during mammalian embryonic development. Although the DNA methylome of early human embryos has been analyzed, some of the key features have not been addressed thus far. Here we performed single-cell DNA methylome sequencing for human preimplantation embryos and found that tens of thousands of genomic loci exhibited de novo DNA methylation. This finding indicates that genome-wide DNA methylation reprogramming during preimplantation development is a dynamic balance between strong global demethylation and drastic focused remethylation. Furthermore, demethylation of the paternal genome is much faster and thorough than that of the maternal genome. From the two-cell to the postimplantation stage, methylation of the paternal genome is consistently lower than that of the maternal genome. We also show that the genetic lineage of early blastomeres can be traced by DNA methylation analysis. Our work paves the way for deciphering the secrets of DNA methylation reprogramming in early human embryos.

Complex Pattern Selectivity in Macaque Primary Visual Cortex Revealed by Large-Scale Two-Photon Imaging

Dec 15，2017

•V1 neuronal responses were studied by using two-photon imaging in awake monkeys •Large population of V1 neurons responded to thousands of visual stimuli •V1 superficial layer neurons exhibited high selectivity to complex patterns

Arabidopsis pollen tube integrity and sperm release are regulated by RALF-mediated signaling

Dec 15，2017

In flowering plants, fertilization requires complex cell-to-cell communication events between the pollen tube and the female reproductive tissues, which are controlled by extracellular signaling molecules interacting with receptors at the pollen tube surface. We found that two such receptors in Arabidopsis, BUPS1 and BUPS2, and their peptide ligands, RALF4 and RALF19, are pollen tube–expressed and are required to maintain pollen tube integrity. BUPS1 and BUPS2 interact with receptors ANXUR1 and ANXUR2 via their ectodomains, and both sets of receptors bind RALF4 and RALF19. These receptor-ligand interactions are in competition with the female-derived ligand RALF34, which induces pollen tube bursting at nanomolar concentrations. We propose that RALF34 replaces RALF4 and RALF19 at the interface of pollen tube–female gametophyte contact, thereby deregulating BUPS-ANXUR signaling and in turn leading to pollen tube rupture and sperm release.

3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations

Dec 05，2017

The Hi-C method is widely used to study the functional roles of the three-dimensional (3D) architecture of genomes. Here, we integrate Hi-C, whole-genome sequencing (WGS) and RNA-seq to study the 3D genome architecture of multiple myeloma (MM) and how it associates with genomic variation and gene expression. Our results show that Hi-C interaction matrices are biased by copy number variations (CNVs) and can be used to detect CNVs. Also, combining Hi-C and WGS data can improve the detection of translocations. We find that CNV breakpoints significantly overlap with topologically associating domain (TAD) boundaries. Compared to normal B cells, the numbers of TADs increases by 25% in MM, the average size of TADs is smaller, and about 20% of genomic regions switch their chromatin A/B compartment types. In summary, we report a 3D genome interaction map of aneuploid MM cells and reveal the relationship among CNVs, translocations, 3D genome reorganization, and gene expression regulation.

CRISPR/Cas9-mediated targeted chromosome elimination

Dec 04，2017

The CRISPR/Cas9 system has become an efficient gene editing method for generating cells carrying precise gene mutations, including the rearrangement and deletion of chromosomal segments. However, whether an entire chromosome could be eliminated by this technology is still unknown.

　