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Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing

Jun 16，2017

Single-cell RNA-seq reveals distinctive functional composition of T cells in HCC Clonal enrichment of infiltrating Tregs and exhausted CD8 T cells in HCC LAYN is linked to the suppressive function of tumor Treg and exhausted CD8 T cells Combined expression and TCR-based analyses show connectivity among T cell subsets

Sperm cells are passive cargo of the pollen tube in plant fertilization

Jun 08，2017

Sperm cells of seed plants have lost their motility and are transported by the vegetative pollen tube cell for fertilization, but the extent to which they regulate their own transportation is a long-standing debate. Here we show that Arabidopsis lacking two bHLH transcription factors produces pollen without sperm cells. This abnormal pollen mostly behaves like the wild type and demonstrates that sperm cells are dispensable for normal pollen tube development.

Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation

Jun 07，2017

Targeting the specific metabolic phenotypes of colorectal cancer stem cells (CRCSCs) is an innovative therapeutic strategy for colorectal cancer (CRC) patients with poor prognosis and relapse. However, the context-dependent metabolic traits of CRCSCs remain poorly elucidated. Here we report that adenylate kinase hCINAP is overexpressed in CRC tissues. Depletion of hCINAP inhibits invasion, self-renewal, tumorigenesis and chemoresistance of CRCSCs with a loss of mesenchymal signature. Mechanistically, hCINAP binds to the C-terminal domain of LDHA, the key regulator of glycolysis, and depends on its adenylate kinase activity to promote LDHA phosphorylation at tyrosine 10, resulting in the hyperactive Warburg effect and the lower cellular ROS level and conferring metabolic advantage to CRCSC invasion. Moreover, hCINAP expression is positively correlated with the level of Y10-phosphorylated LDHA in CRC patients. This study identifies hCINAP as a potent modulator of metabolic reprogramming in CRCSCs and a promising drug target for CRC invasion and metastasis.

Low genetic diversity and strong population structure shaped by anthropogenic habitat fragmentation in a critically endangered primate, Trachypithecus leucocephalus

May 19，2017

Habitat fragmentation may strongly impact population genetic structure and reduce the genetic diversity and viability of small and isolated populations. The white-headed langur (Trachypithecus leucocephalus) is a critically endangered primate species living in a highly fragmented and human-modified habitat in southern China. We examined the population genetic structure and genetic diversity of the species and investigated the environmental and anthropogenic factors that may have shaped its population structure. We used 214 unique multi-locus genotypes from 41 social groups across the main distribution area of T. leucocephalus, and found strong genetic structure and significant genetic differentiation among local populations. Our landscape genetic analyses using a causal modelling framework suggest that a large habitat gap and geographical distance represent the primary landscape elements shaping genetic structure, yet high levels of genetic differentiation also exist between patches separated by a small habitat gap or road. This is the first comprehensive study that has evaluated the population genetic structure and diversity of T. leucocephalus using nuclear markers. Our results indicate strong negative impacts of anthropogenic land modifications and habitat fragmentation on primate genetic connectivity between forest patches. Our analyses suggest that two management units of the species could be defined, and indicate that habitat continuity should be enforced and restored to reduce genetic isolation and enhance population viability.

Single-cell sequencing deciphers a convergent evolution of copy number alterations from primary to circulating tumour cells

May 17，2017

Copy number alteration (CNA) is a major contributor to genome instability, a hallmark of cancer. Here we studied genomic alterations in single primary tumour cells and circulating tumour cells (CTCs) from the same patient. Single-nucleotide variations (SNVs) in single cells from both samples occurred sporadically, whereas CNAs among primary tumour cells emerged accumulatively rather than abruptly, converging toward that of CTCs. Focal CNAs affecting MYC gene and PTEN gene were observed only in a minor portion of primary tumour cells but were present in all CTCs, suggesting a strong selection toward metastasis. Single-cell structural variation (SV) analyses revealed a two-step mechanism, a complex rearrangement followed by gene amplification, for the simultaneous formation of anomalous CNAs in multiple chromosome regions. Integrative CNA analyses of 97 CTCs from 23 patients confirmed the convergence of CNAs and revealed single, concurrent, and mutually exclusive CNAs that could be the driving events in cancer metastasis.

Crystal Structure of Tetrameric Arabidopsis MYC2 Reveals the Mechanism of Enhanced Interaction with DNA

May 17，2017

Structure of Arabidopsis bHLH MYC2-G-box DNA complex MYC2 forms a cis-tetramer, whereas MYC3 forms a dimer in solution Tetramerization of MYC2 enhances DNA binding and transcription activation MYC2 tetramer has potential to form DNA looping

Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers

Apr 29，2017

Characterization of human microRNAs which target the cell-cycle machinery Profiling cell-cycle-targeting miRNAs against 122 human cancer cell lines from CCLE Algorithm to predict the response of tumors to cell-cycle-targeting miRNAs In vivo delivery of cell-cycle-targeting miRNAs inhibits cancer growth

Single-Cell RNA-Seq Analysis Maps Development of Human Germline Cells and Gonadal Niche Interactions

Apr 28，2017

•RNA sequencing of 2,167 single FGCs identifies multiple stages in individual embryos •Transcriptome landscapes decode TF networks underlying distinct developmental stages •Reciprocal BMP and Notch signaling occurs between FGCs and their niche cells •Female embryos contain four stages of FGCs, even in later developmental stages

Sap1 is a replication-initiation factor essential for the assembly of pre-replicative complex in the fission yeast Schizosaccharomyces pombe

Apr 27，2017

A central step in the initiation of chromosomal DNA replication in eukaryotes is the assembly of pre-replicative complex (pre-RC) at late M and early G1 phase of the cell cycles. Since 1973, four proteins or protein complexes, including cell division control protein 6 (Cdc6)/Cdc18, minichromosome maintenance protein complex, origin recognition complex (ORC), and Cdt1, are known components of the pre-RC. Previously, we reported that a non-ORC protein binds to the essential element Δ9 of the Schizosaccharomyces pombe DNA-replication origin ARS3001. In this study, we identified that the non-ORC protein is Sap1. Like ORC, Sap1 binds to DNA origins during cell growth cycles. But unlike ORC, which binds to asymmetric AT-rich sequences through its nine AT-hook motifs, Sap1 preferentially binds to a DNA sequence of 5′-(A/T)n(C/G)(A/T)9–10(G/C)(A/T)n-3′ (n ≥ 1). We also found that Sap1 and ORC physically interact. We further demonstrated that Sap1 is required for the assembly of the pre-RC because of its essential role in recruiting Cdc18 to DNA origins. Thus, we conclude that Sap1 is a replication-initiation factor that directly participates in the assembly of the pre-RC. DNA-replication origins in fission yeast are defined by possessing two essential elements with one bound by ORC and the other by Sap1.

Direct Visualization of RNA-DNA Primer Removal from Okazaki Fragments Provides Support for Flap Cleavage and Exonucleolytic Pathways in Eukaryotic Cells

Apr 27，2017

During DNA replication in eukaryotic cells, short single-stranded DNA segments known as Okazaki fragments are first synthesized on the lagging strand. The Okazaki fragments originate from ∼35-nucleotide-long RNA-DNA primers. After Okazaki fragment synthesis, these primers must be removed to allow fragment joining into a continuous lagging strand. To date, the models of enzymatic machinery that removes the RNA-DNA primers have come almost exclusively from biochemical reconstitution studies and some genetic interaction assays, and there is little direct evidence to confirm these models. One obstacle to elucidating Okazaki fragment processing has been the lack of methods that can directly examine primer removal in vivo. In this study, we developed an electron microscopy assay that can visualize nucleotide flap structures on DNA replication forks in fission yeast (Schizosaccharomyces pombe). With this assay, we first demonstrated the generation of flap structures during Okazaki fragment processing in vivo. The mean and median lengths of the flaps in wild-type cells were ∼51 and ∼41 nucleotides, respectively. We also used yeast mutants to investigate the impact of deleting key DNA replication nucleases on these flap structures. Our results provided direct in vivo evidence for a previously proposed flap cleavage pathway and the critical function of Dna2 and Fen1 in cleaving these flaps. In addition, we found evidence for another previously proposed exonucleolytic pathway involving RNA-DNA primer digestion by exonucleases RNase H2 and Exo1. Taken together, our observations suggest a dual mechanism for Okazaki fragment maturation in lagging strand synthesis and establish a new strategy for interrogation of this fascinating process.

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

Apr 07，2017

A chemical cocktail enables derivation of EPS cells from both humans and mice A single mouse EPS cell generates both embryonic and extraembryonic lineages in vivo Mouse EPS cells show robust and superior chimeric ability at the single cell level Human EPS cells show interspecies chimeric competency in mouse conceptuses

The Super Elongation Complex Drives Neural Stem Cell Fate Commitment

Mar 28，2017

Super elongation complex (SEC) subunits are highly expressed in neural stem cells SEC forms a positive feedback loop with Notch signaling in promoting NSC self-renewal Overactivation of SEC induces neural progenitor dedifferentiation and tumorigenesis SEC acts as an intrinsic amplifier driving neural stem cell fate commitment

　