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Lysosomal Trafficking, Antigen Presentation, and Microbial Killing Are Controlled by the Arf-like GTPase Arl8b

IMMUNITY 2011年第2期35卷 182-193页

作者： Garg, Salil Sharma, Mahak Ung, Cindy Tuli, Amit Barral, Duarte C. Hava, David L. Veerapen, Natacha Besra, Gurdyal S. Hacohen, Nir Brenner, Michael B. Brigham & Womens Hosp Dept Med Div Rheumatol Allergy & Immunol Boston MA 02115 USA Harvard Div Med Sci Grad Program Immunol Boston MA 02115 USA Harvard MIT MD PhD Program Boston MA 02115 USA Univ Birmingham Sch Biosci Birmingham W Midlands England Broad Inst MIT & Harvard Cambridge MA 02142 USA Massachusetts Gen Hosp Ctr Immunol & Inflammatory Dis Charlestown MA 02129 USA

Antigen presentation and microbial killing are critical arms of host defense that depend upon cargo trafficking into lysosomes. Yet, the molecular regulators of traffic into lysosomes are only partly understood. Here, using a lysosome-dependent immunological screen of a trafficking shRNA library, we identified the Art-like GTPase Arl8b as a critical regulator of cargo delivery to lysosomes. Homotypic fusion and vacuole protein sorting (HOPS) complex members were identified as effectors of Arl8b and were dependent on Arl8b for recruitment to lysosomes, suggesting that Arl8b-HOPS plays a general role in directing traffic to lysosomes. Moreover, the formation of CD1 antigen-presenting complexes in lysosomes, their delivery to the plasma membrane, and phagosome-lysosome fusion were all markedly impaired in Arl8b silenced cells resulting in corresponding defects in T cell activation and microbial killing. Together, these results define Arl8b as a key regulator of lysosomal cellular and immunological functions.

关键词： ADP-Ribosylation Factors/genetics ADP-Ribosylation Factors/immunology ADP-Ribosylation Factors/metabolism Antigen Presentation/genetics Antigens/immunology Antigens/metabolism Antigens, CD1d/metabolism Cytokines/genetics Cytokines/metabolism Cytotoxicity, Immunologic/genetics HeLa Cells Humans Lymphocyte Activation/genetics Lymphocyte Activation/genetics Lysosomes/metabolism Natural Killer T-Cells/immunology Natural Killer T-Cells/metabolism Natural Killer T-Cells/pathology Protein Binding/genetics Protein Transport/genetics Proteolipids/immunology Proteolipids/metabolism rab GTP-Binding Proteins/metabolism RNA, Small Interfering/genetics RNA, Small Interfering/genetics Vesicular Transport Proteins/metabolism

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Charting cellular identity during human in vitro β-cell differentiation

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NATURE 2019年第7756期569卷 368-+页

作者： Veres, Adrian Faust, Aubrey L. Bushnell, Henry L. Engquist, Elise N. Kenty, Jennifer Hyoje-Ryu Harb, George Poh, Yeh-Chuin Sintov, Elad Gurtler, Mads Pagliuca, Felicia W. Peterson, Quinn P. Melton, Douglas A. Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA MIT Harvard Mit Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard Univ Harvard Syst Biol PhD Program Cambridge MA 02138 USA Semma Therapeut Cambridge MA USA Mayo Clin Dept Physiol & Biomed Engn Rochester MN USA Howard Hughes Med Inst Chevy Chase MD 20815 USA

In vitro differentiation of human stem cells can produce pancreatic beta-cells;the loss of this insulin-secreting cell type underlies type 1 diabetes. Here, as a step towards understanding this differentiation process, we report the transcriptional profiling of more than 100,000 human cells undergoing in vitro beta-cell differentiation, and describe the cells that emerged. We resolve populations that correspond to beta-cells, alpha-like poly-hormonal cells, non-endocrine cells that resemble pancreatic exocrine cells and a previously unreported population that resembles enterochromaffin cells. We show that endocrine cells maintain their identity in culture in the absence of exogenous growth factors, and that changes in gene expression associated with in vivo beta-cell maturation are recapitulated in vitro. We implement a scalable re-aggregation technique to deplete non-endocrine cells and identify CD49a (also known as ITGA1) as a surface marker of the beta-cell population, which allows magnetic sorting to a purity of 80%. Finally, we use a high-resolution sequencing time course to characterize gene-expression dynamics during the induction of human pancreatic endocrine cells, from which we develop a lineage model of in vitro beta-cell differentiation. This study provides a perspective on human stem-cell differentiation, and will guide future endeavours that focus on the differentiation of pancreatic islet cells, and their applications in regenerative medicine.

关键词： Embryonic stem cells Regenerative medicine RNA sequencing Stem-cell biotechnology Stem-cell differentiation

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Insights into Neurodegeneration in Parkinson's Disease from Single-Cell and Spatial Genomics

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MOVEMENT DISORDERS 2023年第4期38卷 518-525页

作者： Kamath, Tushar Macosko, Evan Z. Broad Inst Stanley Ctr Psychiat Res Cambridge MA USA Harvard Med Sch Cambridge MA USA Harvard Univ Harvard MIT MD PhD Program Cambridge MA USA Massachusetts Gen Hosp Dept Psychiat Boston MA USA Broad Inst Stanley Ctr Psychiat Res 75 Ames St Cambridge MA 02139 USA

Parkinson's disease (PD) is pathologically defined by the death of dopaminergic (DA) neurons within the pars compacta of the substantia nigra. To date, the cause of this multifaceted disease remains largely unclear, which may contribute in part to a current lack of disease-modifying therapies. Recent advances in single-cell and spatial genomic profiling tools have provided powerful new ways to measure cellular state changes in brain diseases. Here, we describe how these tools have offered insight into these complex disorders and highlight a recently performed comprehensive study of DA neuron susceptibility in PD. The data generated by this recent work provide evidence for the role of specific pathways and common genetic variants resulting in the loss of a critical DA subtype in PD. We conclude by outlining a set of basic and translational opportunities that arise from those data and insights gathered from this work. (c) 2023 International Parkinson and Movement Disorder Society.

关键词： Parkinson's disease dopaminergic substantia nigra

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Accurate detection of mosaic variants in sequencing data without matched controls

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NATURE BIOTECHNOLOGY 2020年第3期38卷 314-+页

作者： Dou, Yanmei Kwon, Minseok Rodin, Rachel E. Cortes-Ciriano, Isidro Doan, Ryan Luquette, Lovelace J. Galor, Alon Bohrson, Craig Walsh, Christopher A. Park, Peter J. Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA USA Harvard Med Sch Dept Neurol Boston MA 02115 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Bioinformat & Integrat Genom PhD Program Boston MA 02115 USA Ludwig Ctr Harvard Boston MA 02215 USA European Bioinformat Inst European Mol Biol Lab Hinxton England

MosaicForecast detects mosaic single-nucleotide variants and indels in human samples. Detection of mosaic mutations that arise in normal development is challenging, as such mutations are typically present in only a minute fraction of cells and there is no clear matched control for removing germline variants and systematic artifacts. We present MosaicForecast, a machine-learning method that leverages read-based phasing and read-level features to accurately detect mosaic single-nucleotide variants and indels, achieving a multifold increase in specificity compared with existing algorithms. Using single-cell sequencing and targeted sequencing, we validated 80-90% of the mosaic single-nucleotide variants and 60-80% of indels detected in human brain whole-genome sequencing data. Our method should help elucidate the contribution of mosaic somatic mutations to the origin and development of disease.

关键词： Computational biology and bioinformatics Genome Genomic analysis Mutation

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Addressing the longitudinal components of surgical treatments

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EUROPEAN JOURNAL OF EPIDEMIOLOGY 2023年第10期38卷 1019-1023页

作者： Messinger, Chelsea J. Madenci, Arin L. Wanis, Kerollos Nashat Harvard TH Chan Sch Publ Hlth Dept Epidemiol 677 Huntington Ave Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Boston Childrens Hosp Dept Surg Boston MA USA Western Univ Dept Surg London ON Canada

Despite their pre- and postoperative components, surgical treatment strategies have typically been cast as point interventions in causal inference research. When longitudinal perioperative components affect outcomes of interest, leaving them unspecified or failing to measure adherence to them complicates the interpretation of effect estimates. Inspired by two recent landmark trials that assessed the risk of stroke or death after transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR), the PARTNER 3 trial and the Evolut Low Risk trial, we discuss possible ways that different postoperative therapies in treatment arms and incomplete adherence to those therapies can impact the interpretation of intention-to-treat effect estimates in surgical trials. We argue that surgical treatments are not necessarily point interventions, and make recommendations for improving the design and analysis of trials involving surgical interventions. Central to these recommendations is the need for investigators to specify and report adherence to longitudinal perioperative treatment components.

关键词： Causal inference Randomized control trial Surgery Transportability Time-varying exposure Adherence

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Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

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CELL 2016年第1期165卷 234-246页

作者： Zhao, Boyang Sedlak, Joseph C. Srinivas, Raja Creixell, Pau Pritchard, Justin R. Tidor, Bruce Lauffenburger, Douglas A. Hemann, Michael T. MIT Computat & Syst Biol Program 77 Massachusetts Ave Cambridge MA 02139 USA MIT David H Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA MIT Comp Sci & Artificial Intelligence Lab 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA ARIAD Pharmaceut Inc Cambridge MA 02139 USA

The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity.'' Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph+ acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.

关键词： CLONAL selection theory DRUG resistance in cancer cells SUBSTANCE abuse -- Relapse CANCER research SENSITIZATION (Neuropsychology)

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Detect and destroy: CRISPR-based technologies for the response against viruses

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CELL HOST & MICROBE 2021年第5期29卷 689-703页

作者： Freije, Catherine A. Sabeti, Pardis C. Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch PhD Program Virol Boston MA 02115 USA Harvard TH Chan Sch Publ Hlth Boston MA 02115 USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Howard Hughes Med Inst Chevy Chase MD 20815 USA Massachusetts Consortium Pathogen Readiness Boston MA 02115 USA

Despite numerous viral outbreaks in the last decade, including a devastating global pandemic, diagnostic and therapeutic technologies remain severely lacking. CRISPR-Cas systems have the potential to address these critical needs in the response against infectious disease. Initially discovered as the bacterial adaptive immune system, these systems provide a unique opportunity to create programmable, sequence-specific technologies for detection of viral nucleic acids and inhibition of viral replication. This review summarizes how CRISPR-Cas systems-in particular the recently discovered DNA-targeting Cas12 and RNA-targeting Cas13, both possessing a unique trans-cleavage activity-are being harnessed for viral diagnostics and therapies. We further highlight the numerous technologies whose development has accelerated in response to the COVID-19 pandemic.

关键词： CRISPR class 2 Cas proteins viruses CRISPR-based antivirals CRISPR-based detection viral diagnostics

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Linked-read analysis identifies mutations in single-cell DNA-sequencing data

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NATURE GENETICS 2019年第4期51卷 749-+页

作者： Bohrson, Craig L. Barton, Alison R. Lodato, Michael A. Rodin, Rachel E. Luquette, Lovelace J. Viswanadham, Vinay V. Gulhan, Doga C. Cortes-Ciriano, Isidro Sherman, Maxwell A. Kwon, Minseok Coulter, Michael E. Galor, Alon Walsh, Christopher A. Park, Peter J. Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Harvard Med Sch Bioinformat & Integrat Genom PhD Program Boston MA 02115 USA Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA USA Harvard Med Sch Dept Neurol Boston MA 02115 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Broad Inst Cambridge MA USA Harvard Med Sch Program Neurosci Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PHD Program Boston MA 02115 USA Univ Cambridge Ctr Mol Sci Informat Dept Chem Cambridge England

Whole-genome sequencing of DNA from single cells has the potential to reshape our understanding of mutational heterogeneity in normal and diseased tissues. However, a major difficulty is distinguishing amplification artifacts from biologically derived somatic mutations. Here, we describe linked-read analysis (LiRA), a method that accurately identifies somatic singlenucleotide variants (sSNVs) by using read-level phasing with nearby germline heterozygous polymorphisms, thereby enabling the characterization of mutational signatures and estimation of somatic mutation rates in single cells.

关键词： Bioinformatics DNA sequencing

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A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

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GENOME BIOLOGY 2014年第11期15卷 1-14页

作者： Herman, Jonathan D. Rice, Daniel P. Ribacke, Ulf Silterra, Jacob Deik, Amy A. Moss, Eli L. Broadbent, Kate M. Neafsey, Daniel E. Desai, Michael M. Clish, Clary B. Mazitschek, Ralph Wirth, Dyann F. Harvard Univ Sch Med Dept Immunol & Infect Dis Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Biol & Biomed Sci Boston MA 02115 USA Harvard MIT Div Hlth Sci & Technol Boston MA 02115 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Harvard Univ FAS Ctr Syst Biol Cambridge MA 02138 USA Uppsala Univ Dept Cell & Mol Biol S-75105 Uppsala Sweden Massachusetts Gen Hosp Ctr Syst Biol Boston MA 02114 USA

Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.

关键词： Proline Malaria Artemisinin tRNA Synthetase Pipecolic Acid

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Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type -specific lineage patterns in human brain

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020年第25期117卷 13886-13895页

作者： Huang, August Yue Li, Pengpeng Rodin, Rachel E. Kim, Sonia N. Dou Yanmei Kenny, Connor J. Akula, Shyam K. Hodge, Rebecca D. Bakken, Trygve E. Miller, Jeremy A. Lein, Ed S. Park, Peter J. Lee, Eunjung Alice Walsh, Christopher A. Boston Childrens Hosp Div Genet & Genom Boston MA 02115 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Boston Childrens Hosp Manton Ctr Orphan Dis Res Boston MA 02115 USA Harvard Med Sch Dept Neurol Boston MA 02115 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02141 USA Harvard Med Sch Program Neurosci Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Program Biol & Biomed Sci Boston MA 02138 USA Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Harvard Med Sch Ludwig Ctr Harvard Boston MA 02115 USA Allen Inst Brain Sci Seattle WA 98109 USA

Elucidating the lineage relationships among different cell types is key to understanding human brain development. Here we de- veloped parallel RNA and DNA analysis after deep sequencing (PRDD-seq), which combines RNA analysis of neuronal cell types with analysis of nested spontaneous DNA somatic mutations as cell lineage markers, identified from joint analysis of single -cell and bulk DNA sequencing by single -cell MosaicHunter (scMH). PRDD-seq enables simultaneous reconstruction of neuronal cell type, cell lineage, and sequential neuronal formation ( ?birthdate ?) in postmortem human cerebral cortex. Analysis of two human brains showed remarkable quantitative details that relate muta- tion mosaic frequency to clonal patterns, confirming an early di- vergence of precursors for excitatory and inhibitory neurons, and an ?inside -out ? layer formation of excitatory neurons as seen in other species. In addition our analysis allows an estimate of excit- atory neuron -restricted precursors (about 10) that generate the excitatory neurons within a cortical column. Inhibitory neurons showed complex, subtype -specific patterns of neurogenesis, in- cluding some patterns of development conserved relative to mouse, but also some aspects of primate cortical interneuron de- velopment not seen in mouse. PRDD-seq can be broadly applied to characterize cell identity and lineage from diverse archival samples with single -cell resolution and in potentially any developmental or disease condition.

关键词： PRDD-seq single-cell MosaicHunter birthdating cortical layer neurodevelopment

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