Jinfeng Liu

Bio: Jinfeng Liu is an academic researcher from Genentech. The author has contributed to research in topics: Structural genomics & Ubiquitin ligase. The author has an hindex of 49, co-authored 84 publications receiving 14839 citations. Previous affiliations of Jinfeng Liu include Columbia University & Structural Genomics Consortium.

The Transcriptional Landscape of the Mammalian Genome

Abstract: This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.

Non-canonical inflammasome activation targets caspase-11

Abstract: Caspase-1 activation by inflammasome scaffolds comprised of intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the adaptor ASC is believed to be essential for production of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 during the innate immune response. Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4) is critical for caspase-1 activation and IL-1β production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11(-/-) mice, exhibited defects in IL-1β production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression. This finding is important because published targeting of the Casp1 gene was done using strain 129 embryonic stem cells. Casp1 and Casp11 are too close in the genome to be segregated by recombination; consequently, the published Casp1(-/-) mice lack both caspase-11 and caspase-1. Interestingly, Casp11(-/-) macrophages secreted IL-1β normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1(-/-)Casp11(129mt/129mt) macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1β regardless of stimulus, confirming an essential role for caspase-1 in IL-1β production. Caspase-11 rather than caspase-1, however, was required for non-canonical inflammasome-triggered macrophage cell death, indicating that caspase-11 orchestrates both caspase-1-dependent and -independent outputs. Caspase-1 activation by non-canonical stimuli required NLRP3 and ASC, but caspase-11 processing and cell death did not, implying that there is a distinct activator of caspase-11. Lastly, loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide. These data highlight a unique pro-inflammatory role for caspase-11 in the innate immune response to clinically significant bacterial infections.

The PredictProtein server

Abstract: PredictProtein (http://www.predictprotein.org) is an Internet service for sequence analysis and the prediction of protein structure and function. Users submit protein sequences or alignments; PredictProtein returns multiple sequence alignments, PROSITE sequence motifs, low-complexity regions (SEG), nuclear localization signals, regions lacking regular structure (NORS) and predictions of secondary structure, solvent accessibility, globular regions, transmembrane helices, coiled-coil regions, structural switch regions, disulfide-bonds, sub-cellular localization and functional annotations. Upon request fold recognition by prediction-based threading, CHOP domain assignments, predictions of transmembrane strands and inter-residue contacts are also available. For all services, users can submit their query either by electronic mail or interactively via the World Wide Web.

Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Abstract: Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.

The Genome of M. Acetivorans Reveals Extensive Metabolic and Physiological Diversity

Abstract: The Archaea remain the most poorly understood domain of life despite their importance to the biosphere. Methanogenesis, which plays a pivotal role in the global carbon cycle, is unique to the Archaea. Each year, an estimated 900 million metric tons of methane are biologically produced, representing the major global source for this greenhouse gas and contributing significantly to global warming (Schlesinger 1997). Methanogenesis is critical to the waste-treatment industry and biologically produced methane also represents an important alternative fuel source. At least two-thirds of the methane in nature is derived from acetate, although only two genera of methanogens are known to be capable of utilizing this substrate. We report here the first complete genome sequence of an acetate-utilizing (acetoclastic) methanogen, Methanosarcina acetivorans C2A. The Methanosarcineae are metabolically and physiologically the most versatile methanogens. Only Methanosarcina species possess all three known pathways for methanogenesis (Fig. ​(Fig.1)1) and are capable of utilizing no less than nine methanogenic substrates, including acetate. In contrast, all other orders of methanogens possess a single pathway for methanogenesis, and many utilize no more than two substrates. Among methanogens, the Methanosarcineae also display extensive environmental diversity. Individual species of Methanosarcina have been found in freshwater and marine sediments, decaying leaves and garden soils, oil wells, sewage and animal waste digesters and lagoons, thermophilic digesters, feces of herbivorous animals, and the rumens of ungulates (Zinder 1993). Figure 1 Three pathways for methanogenesis. Methanogenesis is a form of anaerobic respiration using a variety of one-carbon (C-1) compounds or acetic acid as a terminal electron acceptor. All three pathways converge on the reduction of methyl-CoM to methane (CH ... The Methanosarcineae are unique among the Archaea in forming complex multicellular structures during different phases of growth and in response to environmental change (Fig. ​(Fig.2).2). Within the Methanosarcineae, a number of distinct morphological forms have been characterized, including single cells with and without a cell envelope, as well as multicellular packets and lamina (Macario and Conway de Macario 2001). Packets and lamina display internal morphological heterogeneity, suggesting the possibility of cellular differentiation. Moreover, it has been suggested that cells within lamina may display differential production of extracellular material, a potential form of cellular specialization (Macario and Conway de Macario 2001). The formation of multicellular structures has been proposed to act as an adaptation to stress and likely plays a role in the ability of Methanosarcina species to colonize diverse environments. Figure 2 Different morphological forms of Methanosarcina acetivorans. Thin-section electron micrographs showing M. acetivorans growing as both single cells (center of micrograph) and within multicellular aggregates (top left, bottom right). Cells were harvested ... Significantly, powerful methods for genetic analysis exist for Methanosarcina species. These tools include plasmid shuttle vectors (Metcalf et al. 1997), very high efficiency transformation (Metcalf et al. 1997), random in vivo transposon mutagenesis (Zhang et al. 2000), directed mutagenesis of specific genes (Zhang et al. 2000), multiple selectable markers (Boccazzi et al. 2000), reporter gene fusions (M. Pritchett and W. Metcalf, unpubl.), integration vectors (Conway de Macario et al. 1996), and anaerobic incubators for large-scale growth of methanogens on solid media (Metcalf et al. 1998). Furthermore, and in contrast to other known methanogens, genetic analysis can be used to study the process of methanogenesis: Because Methanosarcina species are able to utilize each of the three known methanogenic pathways, mutants in a single pathway are viable (M. Pritchett and W. Metcalf, unpubl.). The availability of genetic methods allowing immediate exploitation of genomic sequence, coupled with the genetic, physiological, and environmental diversity of M. acetivorans make this species an outstanding model organism for the study of archaeal biology. For these reasons, we set out to study the genome of M. acetivorans.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

A framework for variation discovery and genotyping using next-generation DNA sequencing data

Abstract: Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Abstract: BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

I-TASSER: a unified platform for automated protein structure and function prediction

Abstract: The iterative threading assembly refinement (I-TASSER) server is an integrated platform for automated protein structure and function prediction based on the sequence-to-structure-to-function paradigm. Starting from an amino acid sequence, I-TASSER first generates three-dimensional (3D) atomic models from multiple threading alignments and iterative structural assembly simulations. The function of the protein is then inferred by structurally matching the 3D models with other known proteins. The output from a typical server run contains full-length secondary and tertiary structure predictions, and functional annotations on ligand-binding sites, Enzyme Commission numbers and Gene Ontology terms. An estimate of accuracy of the predictions is provided based on the confidence score of the modeling. This protocol provides new insights and guidelines for designing of online server systems for the state-of-the-art protein structure and function predictions. The server is available at http://zhanglab.ccmb.med.umich.edu/I-TASSER.

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Abstract: We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.