Search results for: Nevan J. Krogan

Items from 1 to 20 out of 63 results

article

Integrative structure determination of histones H3 and H4 using genetic interactions

Ignacia Echeverria, Hannes Braberg, Nevan J. Krogan, Andrej Sali

The FEBS Journal > 290 > 10 > 2565 - 2575

Integrative structure modeling is increasingly used for determining the architectures of biological assemblies, especially those that are structurally heterogeneous. Recently, we reported on how to convert in vivo genetic interaction measurements into spatial restraints for structural modeling: first, phenotypic profiles are generated for each point mutation and thousands of gene deletions or environmental...

article

Mapping genetic interactions in cancer: a road to rational combination therapies

Beril Tutuncuoglu, Nevan J. Krogan

Genome Medicine > 2019 > 11 > 1 > 1-12

The discovery of synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) inhibitors and BRCA genes, which are involved in homologous recombination, led to the approval of PARP inhibition as a monotherapy for patients with BRCA1/2-mutated breast or ovarian cancer. Studies following the initial observation of synthetic lethality demonstrated that the reach of PARP inhibitors is well...

article

An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses

Bennett H. Penn, Zoe Netter, Jeffrey R. Johnson, John Von Dollen, more

Molecular Cell > 2018 > 71 > 4 > 637-648.e5

Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein...

article

The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

A. Jeremy Willsey, Montana T. Morris, Sheng Wang, Helen R. Willsey, more

Cell > 2018 > 174 > 3 > 505-520

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path...

article

The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells

Gundula Streubel, Ariane Watson, Sri Ganesh Jammula, Andrea Scelfo, more

Molecular Cell > 2018 > 70 > 2 > 371-379.e5

The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12...

article

Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits

Ruchi Masand, Esther Paulo, Dongmei Wu, Yangmeng Wang, more

Cell Metabolism > 2018 > 27 > 3 > 616-629.e4

Brown adipose tissue (BAT) thermogenesis is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that BAT-specific liver kinase b1 knockout (Lkb1^BKO) mice exhibited impaired BAT mitochondrial respiration and thermogenesis but reduced adiposity and liver triglyceride accumulation under high-fat-diet...

article

SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

Daniela Boehm, Mark Jeng, Gregory Camus, Andrea Gramatica, more

Cell Host & Microbe > 2017 > 21 > 5 > 569-579.e6

Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme...

article

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells

Braden T. Lobingier, Ruth Hüttenhain, Kelsie Eichel, Kenneth B. Miller, more

Cell > 2017 > 169 > 2 > 350-360.e12

Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial...

article

Inhibition of CRISPR-Cas9 with Bacteriophage Proteins

Benjamin J. Rauch, Melanie R. Silvis, Judd F. Hultquist, Christopher S. Waters, more

Cell > 2017 > 168 > 1-2 > 150-158.e10

Bacterial CRISPR-Cas systems utilize sequence-specific RNA-guided nucleases to defend against bacteriophage infection. As a countermeasure, numerous phages are known that produce proteins to block the function of class 1 CRISPR-Cas systems. However, currently no proteins are known to inhibit the widely used class 2 CRISPR-Cas9 system. To find these inhibitors, we searched cas9-containing bacterial...

article

The mTOR Complex Controls HIV Latency

Emilie Besnard, Shweta Hakre, Martin Kampmann, Hyung W. Lim, more

Cell Host & Microbe > 2016 > 20 > 6 > 785-797

A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR...

article

A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export

Danyang Gong, Yong Hoon Kim, Yuchen Xiao, Yushen Du, more

Cell Host & Microbe > 2016 > 20 > 5 > 642-653

Nuclear mRNA export is highly regulated to ensure accurate cellular gene expression. Viral inhibition of cellular mRNA export can enhance viral access to the cellular translation machinery and prevent anti-viral protein production but is generally thought to be nonselective. We report that ORF10 of Kaposi’s sarcoma-associated herpesvirus (KSHV), a nuclear DNA virus, inhibits mRNA export in a transcript-selective...

article

A Cas9 Ribonucleoprotein Platform for Functional Genetic Studies of HIV-Host Interactions in Primary Human T Cells

Judd F. Hultquist, Kathrin Schumann, Jonathan M. Woo, Lara Manganaro, more

Cell Reports > 2016 > 17 > 5 > 1438-1452

New genetic tools are needed to understand the functional interactions between HIV and human host factors in primary cells. We recently developed a method to edit the genome of primary CD4⁺ T cells by electroporation of CRISPR/Cas9 ribonucleoproteins (RNPs). Here, we adapted this methodology to a high-throughput platform for the efficient, arrayed editing of candidate host factors. CXCR4 or CCR5 knockout...

article

CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs

Mohammad A. Mandegar, Nathaniel Huebsch, Ekaterina B. Frolov, Edward Shin, more

Cell Stem Cell > 2016 > 18 > 4 > 541-553

Developing technologies for efficient and scalable disruption of gene expression will provide powerful tools for studying gene function, developmental pathways, and disease mechanisms. Here, we develop clustered regularly interspaced short palindromic repeat interference (CRISPRi) to repress gene expression in human induced pluripotent stem cells (iPSCs). CRISPRi, in which a doxycycline-inducible...

article

Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection

Nicholas S. Heaton, Natasha Moshkina, Romain Fenouil, Thomas J. Gardner, more

Immunity > 2016 > 44 > 2 > 438

article

Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection

Nicholas S. Heaton, Natasha Moshkina, Romain Fenouil, Thomas J. Gardner, more

Immunity > 2016 > 44 > 1 > 46-58

Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease...

article

CDK11 in TREX/THOC Regulates HIV mRNA 3′ End Processing

Vladimir Pak, Tristan T. Eifler, Stefanie Jäger, Nevan J. Krogan, more

Cell Host & Microbe > 2015 > 18 > 5 > 560-570

Transcriptional cyclin-dependent kinases play important roles in eukaryotic gene expression. CDK7, CDK9 (P-TEFb), and CDK13 are also critical for HIV replication. However, the function of CDK11 remained enigmatic. In this report, we determined that CDK11 regulates the cleavage and polyadenylation (CPA) of all viral transcripts. CDK11 was found associated with the TREX/THOC, which recruited this kinase...

article

Comparative mapping of host–pathogen protein–protein interactions

Priya S Shah, Jason A Wojcechowskyj, Manon Eckhardt, Nevan J Krogan

Current Opinion in Microbiology > 2015 > 27 > Complete > 62-68

Pathogens usurp a variety of host pathways via protein–protein interactions to ensure efficient pathogen replication. Despite the existence of an impressive toolkit of systematic and unbiased approaches, we still lack a comprehensive list of these PPIs and an understanding of their functional implications. Here, we highlight the importance of harnessing genetic diversity of hosts and pathogens for...

article

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection

Kathleen M. Mirrashidi, Cherilyn A. Elwell, Erik Verschueren, Jeffrey R. Johnson, more

Cell Host & Microbe > 2015 > 18 > 1 > 109-121

Chlamydia trachomatis is a leading cause of genital and ocular infections for which no vaccine exists. Upon entry into host cells, C. trachomatis resides within a membrane-bound compartment—the inclusion—and secretes inclusion membrane proteins (Incs) that are thought to modulate the host-bacterium interface. To expand our understanding of Inc function(s), we subjected putative C. trachomatis Incs...

article

Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity

Joshua R. Kane, David J. Stanley, Judd F. Hultquist, Jeffrey R. Johnson, more

Cell Reports > 2015 > 11 > 8 > 1236-1250

HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL) complex as well as the non-canonical cofactor CBFβ, to antagonize APOBEC3 antiviral proteins. Non-canonical cofactor recruitment to CRL complexes by viral factors, to date, has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical,...

article

The Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer

Nevan J. Krogan, Scott Lippman, David A. Agard, Alan Ashworth, more

Molecular Cell > 2015 > 58 > 4 > 690-698

Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly...

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Search results for: Nevan J. Krogan

Integrative structure determination of histones H3 and H4 using genetic interactions

Mapping genetic interactions in cancer: a road to rational combination therapies

An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses

The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells

Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits

SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells

Inhibition of CRISPR-Cas9 with Bacteriophage Proteins

The mTOR Complex Controls HIV Latency

A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export

A Cas9 Ribonucleoprotein Platform for Functional Genetic Studies of HIV-Host Interactions in Primary Human T Cells

CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs

Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection

Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection

CDK11 in TREX/THOC Regulates HIV mRNA 3′ End Processing

Comparative mapping of host–pathogen protein–protein interactions

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection

Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity

The Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer

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