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Article ; Online: Deciphering microglia phenotypes in health and disease.

Balak, Christopher D / Han, Claudia Z / Glass, Christopher K

Current opinion in genetics & development

2024 Volume 84, Page(s) 102146

Abstract: Microglia are the major immune cells of the central nervous system (CNS) that perform numerous adaptive functions required for normal CNS development and homeostasis but are also linked to neurodegenerative and behavioral diseases. Microglia development ... ...

Abstract	Microglia are the major immune cells of the central nervous system (CNS) that perform numerous adaptive functions required for normal CNS development and homeostasis but are also linked to neurodegenerative and behavioral diseases. Microglia development and function are strongly influenced by brain environmental signals that are integrated at the level of transcriptional enhancers to drive specific programs of gene expression. Here, we describe a conceptual framework for how lineage-determining and signal-dependent transcription factors interact to select and regulate the ensembles of enhancers that determine microglia development and function. We then highlight recent findings that advance these concepts and conclude with a consideration of open questions that represent some of the major hurdles to be addressed in the future.
MeSH term(s)	Humans ; Microglia/physiology ; Neurodegenerative Diseases/genetics ; Central Nervous System ; Brain ; Phenotype
Language	English
Publishing date	2024-01-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2023.102146
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Article ; Online: Human microglia phenotypes in the brain associated with HIV infection.

Schlachetzki, Johannes C M / Zhou, Yi / Glass, Christopher K

Current opinion in neurobiology

2022 Volume 77, Page(s) 102637

Abstract: Cognitive impairment in individuals infected with HIV is highly prevalent despite life-long antiretroviral therapy. A growing line of evidence suggests that the human brain serves as a sanctuary for HIV persistence. Microglia, the innate immune cells of ... ...

Abstract	Cognitive impairment in individuals infected with HIV is highly prevalent despite life-long antiretroviral therapy. A growing line of evidence suggests that the human brain serves as a sanctuary for HIV persistence. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for HIV and drive the pathogenesis of HIV-associated neurocognitive disorders. Here, we highlight recent advances in understanding microglia diversity in HIV regarding their epigenome, transcriptome, and function.
MeSH term(s)	Humans ; HIV Infections/complications ; Microglia ; Brain ; Phenotype
Language	English
Publishing date	2022-10-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1078046-4
ISSN	1873-6882 ; 0959-4388
ISSN (online)	1873-6882
ISSN	0959-4388
DOI	10.1016/j.conb.2022.102637
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Zs.A 3260: Show issues

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Article ; Online: Deep learning predicts the impact of regulatory variants on cell-type-specific enhancers in the brain.

Zheng, An / Shen, Zeyang / Glass, Christopher K / Gymrek, Melissa

Bioinformatics advances

2023 Volume 3, Issue 1, Page(s) vbad002

Abstract: Motivation: Previous studies have shown that the heritability of multiple brain-related traits and disorders is highly enriched in transcriptional enhancer regions. However, these regions often contain many individual variants, while only a subset of ... ...

Abstract	Motivation: Previous studies have shown that the heritability of multiple brain-related traits and disorders is highly enriched in transcriptional enhancer regions. However, these regions often contain many individual variants, while only a subset of them are likely to causally contribute to a trait. Statistical fine-mapping techniques can identify putative causal variants, but their resolution is often limited, especially in regions with multiple variants in high linkage disequilibrium. In these cases, alternative computational methods to estimate the impact of individual variants can aid in variant prioritization. Results: Here, we develop a deep learning pipeline to predict cell-type-specific enhancer activity directly from genomic sequences and quantify the impact of individual genetic variants in these regions. We show that the variants highlighted by our deep learning models are targeted by purifying selection in the human population, likely indicating a functional role. We integrate our deep learning predictions with statistical fine-mapping results for 8 brain-related traits, identifying 63 distinct candidate causal variants predicted to contribute to these traits by modulating enhancer activity, representing 6% of all genome-wide association study signals analyzed. Overall, our study provides a valuable computational method that can prioritize individual variants based on their estimated regulatory impact, but also highlights the limitations of existing methods for variant prioritization and fine-mapping. Availability and implementation: The data underlying this article, nucleotide-level importance scores, and code for running the deep learning pipeline are available at https://github.com/Pandaman-Ryan/AgentBind-brain. Contact: mgymrek@ucsd.edu. Supplementary information: Supplementary data are available at
Language	English
Publishing date	2023-01-12
Publishing country	England
Document type	Journal Article
ISSN	2635-0041
ISSN (online)	2635-0041
DOI	10.1093/bioadv/vbad002
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Article ; Online: Immune memory in the brain.

Nott, Alexi / Glass, Christopher K

Nature

2018 Volume 556, Issue 7701, Page(s) 312–313

MeSH term(s)	Brain ; Immunologic Memory ; Memory ; Memory Disorders
Language	English
Publishing date	2018-03-21
Publishing country	England
Document type	News ; Comment
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/d41586-018-03800-6
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Article ; Online: Exploiting dynamic enhancer landscapes to decode macrophage and microglia phenotypes in health and disease.

Troutman, Ty D / Kofman, Eric / Glass, Christopher K

Molecular cell

2021 Volume 81, Issue 19, Page(s) 3888–3903

Abstract: The development and functional potential of metazoan cells is dependent on combinatorial roles of transcriptional enhancers and promoters. Macrophages provide exceptionally powerful model systems for investigation of mechanisms underlying the activation ... ...

Abstract	The development and functional potential of metazoan cells is dependent on combinatorial roles of transcriptional enhancers and promoters. Macrophages provide exceptionally powerful model systems for investigation of mechanisms underlying the activation of cell-specific enhancers that drive transitions in cell fate and cell state. Here, we review recent advances that have expanded appreciation of the diversity of macrophage phenotypes in health and disease, emphasizing studies of liver, adipose tissue, and brain macrophages as paradigms for other tissue macrophages and cell types. Studies of normal tissue-resident macrophages and macrophages associated with cirrhosis, obese adipose tissue, and neurodegenerative disease illustrate the major roles of tissue environment in remodeling enhancer landscapes to specify the development and functions of distinct macrophage phenotypes. We discuss the utility of quantitative analysis of environment-dependent changes in enhancer activity states as an approach to discovery of regulatory transcription factors and upstream signaling pathways.
MeSH term(s)	Animals ; Cell Lineage ; Cellular Microenvironment ; Enhancer Elements, Genetic ; Humans ; Macrophages/metabolism ; Macrophages/pathology ; Microglia/metabolism ; Microglia/pathology ; Phenotype ; Promoter Regions, Genetic ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptional Activation
Chemical Substances	Transcription Factors
Language	English
Publishing date	2021-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2021.08.004
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Zs.A 5055: Show issues

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Article ; Online: Genetic and genomic approaches to understanding macrophage identity and function.

Glass, Christopher K

Arteriosclerosis, thrombosis, and vascular biology

2015 Volume 35, Issue 4, Page(s) 755–762

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 ... ...

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.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Lineage ; Gene Expression Regulation ; Genetic Variation ; Genomics/methods ; Genotype ; Humans ; Macrophages/classification ; Macrophages/metabolism ; Phenotype ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Lectures ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.114.304051
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Article ; Online: Nuclei isolation of multiple brain cell types for omics interrogation.

Nott, Alexi / Schlachetzki, Johannes C M / Fixsen, Bethany R / Glass, Christopher K

Nature protocols

2021 Volume 16, Issue 3, Page(s) 1629–1646

Abstract: We present a nuclei isolation protocol for genomic and epigenomic interrogation of multiple cell type populations in the human and rodent brain. The nuclei isolation protocol allows cell type-specific profiling of neurons, microglia, oligodendrocytes, ... ...

Abstract	We present a nuclei isolation protocol for genomic and epigenomic interrogation of multiple cell type populations in the human and rodent brain. The nuclei isolation protocol allows cell type-specific profiling of neurons, microglia, oligodendrocytes, and astrocytes, being compatible with fresh and frozen samples obtained from either resected or postmortem brain tissue. This 2-day procedure consists of tissue homogenization with fixation, nuclei extraction, and antibody staining followed by fluorescence-activated nuclei sorting (FANS) and does not require specialized skillsets. Cell type-specific nuclei populations can be used for downstream omic-scale sequencing applications with an emphasis on epigenomic interrogation such as histone modifications, transcription factor binding, chromatin accessibility, and chromosome architecture. The nuclei isolation protocol enables translational examination of archived healthy and diseased brain specimens through utilization of existing medical biorepositories.
MeSH term(s)	Animals ; Astrocytes/metabolism ; Brain/metabolism ; Brain Chemistry/physiology ; Cell Nucleus/chemistry ; Cell Nucleus/metabolism ; Chromatin/metabolism ; Epigenomics/methods ; Flow Cytometry/methods ; Genomics/methods ; Humans ; Neurons/metabolism ; Protein Processing, Post-Translational/physiology
Chemical Substances	Chromatin
Language	English
Publishing date	2021-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2244966-8
ISSN	1750-2799 ; 1754-2189
ISSN (online)	1750-2799
ISSN	1754-2189
DOI	10.1038/s41596-020-00472-3
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Article ; Online: Monocyte Regulation in Homeostasis and Malignancy.

Robinson, Amy / Han, Claudia Z / Glass, Christopher K / Pollard, Jeffrey W

Trends in immunology

2021 Volume 42, Issue 2, Page(s) 104–119

Abstract: Monocytes are progenitors to macrophages and a subclass of dendritic cells (monocyte-derived dendritic cells, MoDCs), but they also act as circulating sensors that respond to environmental changes and disease. Technological advances have defined the ... ...

Abstract	Monocytes are progenitors to macrophages and a subclass of dendritic cells (monocyte-derived dendritic cells, MoDCs), but they also act as circulating sensors that respond to environmental changes and disease. Technological advances have defined the production of classical monocytes in the bone marrow through the identification of lineage-determining transcription factors (LDTFs) and have proposed alternative routes of differentiation. Monocytes released into the circulation can be recruited to tissues by specific chemoattractants where they respond to sequential niche-specific signals that determine their differentiation into terminal effector cells. New aspects of monocyte biology in the circulation are being revealed, exemplified by the influence of cancer on the systemic alteration of monocyte subset abundance and transcriptional profiles. These changes can act to enhance the metastatic spread of primary cancers and may offer therapeutic opportunities.
MeSH term(s)	Cell Differentiation ; Dendritic Cells ; Homeostasis ; Humans ; Macrophages ; Monocytes ; Neoplasms
Language	English
Publishing date	2021-01-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2020.12.001
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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Shared Mechanisms between Cardiovascular Disease and NAFLD.

Huang, Daniel Q / Downes, Michael / Evans, Ronald M / Witztum, Joseph L / Glass, Christopher K / Loomba, Rohit

Seminars in liver disease

2022 Volume 42, Issue 4, Page(s) 455–464

Abstract: The burden of nonalcoholic fatty liver disease (NAFLD) is rising globally. Cardiovascular disease is the leading cause of death in patients with NAFLD. Nearly half of individuals with NAFLD have coronary heart disease, and more than a third have carotid ... ...

Abstract	The burden of nonalcoholic fatty liver disease (NAFLD) is rising globally. Cardiovascular disease is the leading cause of death in patients with NAFLD. Nearly half of individuals with NAFLD have coronary heart disease, and more than a third have carotid artery atherosclerosis. Individuals with NAFLD are at a substantially higher risk of fatal and nonfatal cardiovascular events. NAFLD and cardiovascular disease share multiple common disease mechanisms, such as systemic inflammation, insulin resistance, genetic risk variants, and gut microbial dysbiosis. In this review, we discuss the epidemiology of cardiovascular disease in NAFLD, and highlight common risk factors. In addition, we examine recent advances evaluating the shared disease mechanisms between NAFLD and cardiovascular disease. In conclusion, multidisciplinary collaborations are required to further our understanding of the complex relationship between NAFLD and cardiovascular disease and potentially identify therapeutic targets.
MeSH term(s)	Humans ; Non-alcoholic Fatty Liver Disease/epidemiology ; Non-alcoholic Fatty Liver Disease/complications ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/etiology ; Risk Factors ; Insulin Resistance ; Inflammation/complications
Language	English
Publishing date	2022-08-25
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	603177-8
ISSN	1098-8971 ; 0272-8087
ISSN (online)	1098-8971
ISSN	0272-8087
DOI	10.1055/a-1930-6658
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Article ; Online: Nature and nurture of tissue-specific macrophage phenotypes.

Hoeksema, Marten A / Glass, Christopher K

Atherosclerosis

2018 Volume 281, Page(s) 159–167

Abstract: Macrophages are key players in immunity and tissue homeostasis but can also contribute to a diverse range of human diseases, including cardiovascular diseases. Enhancers, cis-acting DNA elements regulating gene activity, have been shown to be crucial for ...

Abstract	Macrophages are key players in immunity and tissue homeostasis but can also contribute to a diverse range of human diseases, including cardiovascular diseases. Enhancers, cis-acting DNA elements regulating gene activity, have been shown to be crucial for control of macrophage development and function. The selection and activities of macrophage-specific enhancers are regulated by the combined actions of lineage determining transcription factors (LDTFs) and signal dependent transcription factors (SDTFs) that are specified by developmental origin and tissue-specific signals. As a consequence, each tissue resident macrophage population adopts a distinct phenotype. In this review, we discuss recent work on how environmental factors affect the activation status of enhancers and can lead to long-lasting epigenetic changes resulting in innate immune memory. Furthermore, we discuss how non-coding genetic variation affects gene expression by altering transcription factor binding through local and domain-wide mechanisms. These findings have implications for interpretation of non-coding risk alleles that are associated with human disease and efforts to target macrophages for therapeutic purposes.
MeSH term(s)	Animals ; Cell Plasticity/genetics ; Cellular Microenvironment ; Epigenesis, Genetic ; Gene-Environment Interaction ; Humans ; Immunity, Innate/genetics ; Immunologic Memory/drug effects ; Macrophage Activation/genetics ; Macrophages/immunology ; Macrophages/metabolism ; Signal Transduction ; Transcription, Genetic
Language	English
Publishing date	2018-10-06
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2018.10.005
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