Christopher K Glass

University of California, San Diego, San Diego, California, United States

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Publications (305)4485.51 Total impact

  • Verena M Link · David Gosselin · Christopher K Glass ·
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    ABSTRACT: Macrophages populate every tissue of the body and play vital roles in homeostasis, pathogen elimination, and tissue healing. These cells possess the ability to adapt to a multitude of abruptly changing and complex environments. Furthermore, different populations of resident tissue macrophages each show their own defining gene signatures. The enhancer repertoire of these cells underlies both the cellular identity of a given subset of resident macrophage population and their ability to dynamically alter, in an efficient manner, their gene expression programs in response to internal and external signals. Notably, transcription is pervasive at active enhancers and enhancer RNAs, or eRNAs, are tightly correlated to regulated transcription of protein-coding genes. Furthermore, selection and establishment of enhancers is a dynamic and plastic process in which activation of intracellular signaling pathways by factors present in a macrophage's environment play a determining role. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the selection and function of enhancers in macrophages and the relevance of studying these mechanisms to gain a better understanding of complex human diseases.
    Cold Spring Harbor Symposia on Quantitative Biology 11/2015; DOI:10.1101/sqb.2015.80.027367

  • Molecular cell 11/2015; 60(3):348-349. DOI:10.1016/j.molcel.2015.10.014 · 14.02 Impact Factor
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    ABSTRACT: The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages.
    Nature Immunology 11/2015; 16(12). DOI:10.1038/ni.3321 · 20.00 Impact Factor
  • Casey E Romanoski · Verena M Link · Sven Heinz · Christopher K Glass ·
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    ABSTRACT: The mammalian genome contains on the order of a million enhancer-like regions that are required to establish the identities and functions of specific cell types. Here, we review recent studies in immune cells that have provided insight into the mechanisms that selectively activate certain enhancers in response to cell lineage and environmental signals. We describe a working model wherein distinct classes of transcription factors define the repertoire of active enhancers in macrophages through collaborative and hierarchical interactions, and discuss important challenges to this model, specifically providing examples from T cells. We conclude by discussing the use of natural genetic variation as a powerful approach for decoding transcription factor combinations that play dominant roles in establishing the enhancer landscapes, and the potential that these insights have for advancing our understanding of the molecular causes of human disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Immunology 08/2015; 36(9). DOI:10.1016/ · 10.40 Impact Factor
  • Christopher K Glass · Joseph L Witztum ·

    Proceedings of the National Academy of Sciences 07/2015; 112(32). DOI:10.1073/pnas.1512413112 · 9.67 Impact Factor
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    ABSTRACT: The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability. RNA-sequencing (RNA-seq) analyses of FACS-purified cells from ISL1-deficient SANs revealed that a number of genes critical for SAN function, including those encoding transcription factors and ion channels, were downstream of ISL1. Chromatin immunoprecipitation assays performed with anti-ISL1 antibodies and chromatin extracts from FACS-purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes required for normal pacemaker function, including subunits of the L-type calcium channel, Ank2, and Tbx3. Other genes implicated in abnormal heart rhythm in humans were also direct ISL1 targets. Together, our results demonstrate that ISL1 regulates approximately one-third of SAN-specific genes, indicate that a combination of ISL1 and other SAN transcription factors could be utilized to generate pacemaker cells, and suggest ISL1 mutations may underlie sick sinus syndrome.
    The Journal of clinical investigation 07/2015; 125(8). DOI:10.1172/JCI68257 · 13.22 Impact Factor
  • Andrea Crotti · Christopher K Glass ·
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    ABSTRACT: Currently, the concept of 'neuroinflammation' includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. The roles of brain-resident and peripheral immune cells in these inflammatory settings are poorly understood, and it is unclear whether neuroinflammation results from immune reaction to neuronal dysfunction/degeneration, and/or represents cell-autonomous phenotypes of dysfunctional immune cells. Here, we review recent studies examining these questions in the context of Huntington's disease (HD), where mutant Huntingtin (HTT) is expressed in both neurons and glia. Insights into the cellular and molecular mechanisms underlying neuroinflammation in HD may provide a better understanding of inflammation in more complex neurodegenerative disorders, and of the contribution of the neuroinflammatory component to neurodegenerative disease pathogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Immunology 05/2015; 36(6). DOI:10.1016/ · 10.40 Impact Factor
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    ABSTRACT: Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.
    eLife Sciences 04/2015; · 9.32 Impact Factor
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    ABSTRACT: eLife digest As we get older, we are more likely to become frail, be less mobile and develop heart disease, diabetes, and other age-related diseases. This is partly due to damage to tissues and organs that accumulates over the course of our lifetime. How quickly we age is controlled both by our genetics and by the environment we live in. It is thought that damage to DNA, proteins, and other molecules in the body caused by chemically active molecules called reactive oxygen species (ROS) can influence aging. ROS are produced during respiration, immune responses, and other important processes in cells, but in excessive amounts they can be extremely harmful. To avoid damage to DNA and other important molecules, cells have several ways to control the levels of ROS. One of the other hallmarks of aging is the development of chronic inflammation in tissues around the body, which is partly triggered by the immune system in response to cell damage. A group of genes called the CD33rSIGLEC genes are involved in controlling inflammation. The genomes of different mammal species carry different numbers of these genes, but it is not clear whether this alters the aging process in these animals. In this study, Schwarz et al. investigated whether the CD33rSIGLEC genes influence the lifespans of mammals. Species with a higher number of CD33rSIGLEC genes generally have a longer lifespan than those with fewer of these genes. Mice that were missing one of these genes and were subjected to inflammation early in life showed signs of accelerated aging and had shortened lifespans compared with normal mice. As predicted, these mice also had higher levels of ROS, which led to a greater amount of damage to the DNA and other molecules in their bodies. Schwarz et al.'s findings suggest that the CD33rSIGLECs co-evolved in mammals to help control the levels of ROS during inflammation, thereby reducing the damage to cells and extending the lifespan of the animals. Given that individual humans have different numbers of working CD33rSIGLEC genes, it would be interesting to see if this influences human lifespan. DOI:
    eLife Sciences 04/2015; 4(4). DOI:10.7554/eLife.06184 · 9.32 Impact Factor
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    Christopher K Glass ·
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    ABSTRACT: A major goal of our laboratory is to understand the molecular mechanisms that underlie the development and functions of diverse macrophage phenotypes in health and disease. Recent studies using genetic and genomic approaches suggest a relatively simple model of collaborative and hierarchical interactions between lineage-determining and signal-dependent transcription factors that enable selection and activation of transcriptional enhancers that specify macrophage identity and function. In addition, we have found that it is possible to use natural genetic variation as a powerful tool for advancing our understanding of how the macrophage deciphers the information encoded by the genome to attain specific phenotypes in a context-dependent manner. Here, I will describe our recent efforts to extend genetic and genomic approaches to investigate the roles of distinct tissue environments in determining the phenotypes of different resident populations of macrophages. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2015; 35(4). DOI:10.1161/ATVBAHA.114.304051 · 6.00 Impact Factor

  • Nature 02/2015; 518(7539):314-6. DOI:10.1038/518314a · 41.46 Impact Factor
  • Casey E. Romanoski · Christopher K. Glass ·

    Nature 02/2015; 518(7539). · 41.46 Impact Factor
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    ABSTRACT: Divergent transcription, in which reverse-oriented transcripts occur upstream of eukaryotic promoters in regions devoid of annotated genes, has been suggested to be a general property of active promoters. Here we show that the human basal RNA polymerase II transcriptional machinery and core promoter are inherently unidirectional and that reverse-oriented transcripts originate from their own cognate reverse-directed core promoters. In vitro transcription analysis and mapping of nascent transcripts in HeLa cells revealed that sequences at reverse start sites are similar to those of their forward counterparts. The use of DNase I accessibility to define proximal promoter borders revealed that about half of promoters are unidirectional and that unidirectional promoters are depleted at their upstream edges of reverse core promoter sequences and their associated chromatin features. Divergent transcription is thus not an inherent property of the transcription process but rather the consequence of the presence of both forward- and reverse-directed core promoters.
    Molecular Cell 02/2015; 57(57):1-11. DOI:10.1016/j.molcel.2014.12.029 · 14.02 Impact Factor
  • Sven Heinz · Casey E Romanoski · Christopher Benner · Christopher K Glass ·
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    ABSTRACT: The human body contains several hundred cell types, all of which share the same genome. In metazoans, much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers. Although mammalian genomes contain millions of potential enhancers, only a small subset of them is active in a given cell type. Cell type-specific enhancer selection involves the binding of lineage-determining transcription factors that prime enhancers. Signal-dependent transcription factors bind to primed enhancers, which enables these broadly expressed factors to regulate gene expression in a cell type-specific manner. The expression of genes that specify cell type identity and function is associated with densely spaced clusters of active enhancers known as super-enhancers. The functions of enhancers and super-enhancers are influenced by, and affect, higher-order genomic organization.
    Nature Reviews Molecular Cell Biology 02/2015; 16(3). DOI:10.1038/nrm3949 · 37.81 Impact Factor
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    ABSTRACT: The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for definitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an omics approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, single nucleotide polymorphisms (SNP), and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profiling liver biopsies, plasma, and urine samples. Using linear discriminant analysis (LDA), a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identification of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of NAFLD. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 01/2015; DOI:10.1194/jlr.P056002 · 4.42 Impact Factor
  • K.A. Allison · C.K. Glass ·
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    ABSTRACT: Macrophages are innate immune cells that sense the presence of pathogens through conserved pattern recognition receptors, which include TLR4. Activation of TLR4 by bacterial lipopolysaccharide induces the expression of thousands of genes that function to initiate infl ammation and coordinate innate and adaptive immune responses. Transcriptional activation of TLR4-responsive genes is mediated by signal-dependent transcription factors, such as NFκB, which bind to DNA regulatory elements termed enhancers. Recent fi ndings indicate that macrophage enhancers are actively transcribed in concert with nearby genes. Similar observations have been reported for other cell types, raising the general question of whether enhancer transcription and/or the resulting enhancer RNAs (eRNAs) are of functional importance. Here, we review the use of macrophage activation as an experimental system for addressing these questions and highlight areas for future research.
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    ABSTRACT: When messenger RNA splicing occurs co-transcriptionally, the potential for kinetic control based on transcription dynamics is widely recognized. Indeed, perturbation studies have reported that when transcription kinetics are perturbed genetically or pharmacologically splice patterns may change. However, whether kinetic control is contributing to the control of splicing within the normal range of physiological conditions remains unknown. We examined if the kinetic determinants for co-transcriptional splicing (CTS) might be reflected in the structure and expression patterns of the genome and epigenome. To identify and then quantitatively relate multiple, simultaneous CTS determinants, we constructed a scalable mathematical model of the kinetic interplay of RNA synthesis and CTS and parameterized it with diverse next generation sequencing (NGS) data. We thus found a variety of CTS determinants encoded in vertebrate genomes and epigenomes, and that these combine variously for different groups of genes such as housekeeping versus regulated genes. Together, our findings indicate that the kinetic basis of splicing is functionally and physiologically relevant, and may meaningfully inform the analysis of genomic and epigenomic data to provide insights that are missed when relying on statistical approaches alone. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 12/2014; 43(2). DOI:10.1093/nar/gku1338 · 9.11 Impact Factor

Publication Stats

54k Citations
4,485.51 Total Impact Points


  • 1988-2015
    • University of California, San Diego
      • • Department of Cellular and Molecular Medicine (CMM)
      • • Department of Medicine
      • • Division of Endocrinology & Metabolism
      San Diego, California, United States
  • 2013
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 1987-2013
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2012
    • University of the Pacific (California - USA)
      Stockton, California, United States
  • 2011
    • Tsinghua University
      • School of Medicine
      Peping, Beijing, China
  • 2010
    • National University (California)
      San Diego, California, United States
    • University of California, Riverside
      • Division of Biomedical Sciences
      Riverside, California, United States
  • 2006
    • Duke University
      Durham, North Carolina, United States
  • 2005
    • Georgia Institute of Technology
      • School of Biology
      Atlanta, Georgia, United States
  • 2002
    • University of Oxford
      Oxford, England, United Kingdom
    • University of Vienna
      Wien, Vienna, Austria
    • CSU Mentor
      Long Beach, California, United States
  • 1991
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1990
    • Washington University in St. Louis
      • Department of Medicine
      San Luis, Missouri, United States