Alzheimer’s disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent ...discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling.
TREM2 has been associated with altered signaling in a number of diseases. This Perspective summarizes our current understanding of this receptor and the pathways it modulates.
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body’s intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect ...the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.
Recent analyses of CNS immune cells in neurodegenerative conditions have identified a subset of microglia showing a unique transcriptional and functional signature, disease-associated microglia (DAM). This perspective proposes a role for DAM as a sensor of early CNS damage and discusses the therapeutic potential of modulating DAM function in CNS diseases.
Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue ...immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.
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•scRNA-seq reveals a dynamic adipose tissue immune cell atlas in mice and humans•Massive induction of a conserved LAM program during obesity•The lipid receptor Trem2 is essential for LAM protective functions•LAMs counteract inflammation, adipocyte hypertrophy, and metabolic disease
A single-cell atlas of human and mouse adipose tissue uncovers protective lipid-associated macrophages (LAMs), which perform lipid uptake and metabolism to prevent adipocyte hypertrophy, inflammation, and systemic metabolic dysregulation in a Trem2 signaling-dependent manner.
We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis ...of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, “gene looping” factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction.
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•Novel method for nucleosome-resolution analysis of chromosome folding•Self-associating domains in yeast are far shorter than those in mammals•Identification of several factors involved in chromosome folding•Evidence for a tri- or tetra-nucleosome motif in chromatin fibers
Mononucleosome resolution mapping of chromosome folding in yeast reveals self-associating domains similar to those found in other organisms. But they are far shorter, with domain size being scaled by gene number rather than linear distance.
Chromatin state dynamics during blood formation Lara-Astiaso, David; Weiner, Assaf; Lorenzo-Vivas, Erika ...
Science (American Association for the Advancement of Science),
08/2014, Letnik:
345, Številka:
6199
Journal Article
Recenzirano
Odprti dostop
Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; ...however, technical limitations impede profiling of homogeneous differentiation intermediates. We developed a high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We identify 48,415 enhancer regions and characterize their dynamics. We find that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in differentiated cells. Combining our enhancer catalog with gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development.
Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and ...transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.
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•Microglia single-cell expression and morphology across 450 million years of evolution•Microglia express a conserved core program, including CNS ligand-receptors pairs•Human microglia show significant heterogeneity in comparison with all mammals•Identification of disease-associated microglia gene expression modules in humans
Single-cell sequencing of microglia across evolutionary timescales leads to definition of a conserved core expression program and identification of heterogeneity in human microglia lacking in other species.
Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also ...implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer’s disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.
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•M-Verse as a global cross-comparison of developing and adult murine brain macrophages•DAM correspond to a fetal-like reprogramming similar to Youth-Associated Microglia•DIMs appear during aging and increase in neurodegenerative diseases•DAM are embryonic derived, whereas DIMs are TREM2-independent monocyte derived
Through 6 scRNA-seq brain dataset integration, the authors generated a myeloid map called M-Verse to delineate macrophage population heterogeneity. M-Verse revealed two distinct macrophage populations expressing published disease-associated microglia (DAM) signature: embryonically derived TREM2-dependent DAM and monocyte-derived TREM2-independent disease inflammatory macrophages (DIMs).
Genome-wide mapping of nucleosomes has revealed a great deal about the relationships between chromatin structure and control of gene expression, and has led to mechanistic hypotheses regarding the ...rules by which chromatin structure is established. High-throughput sequencing has recently become the technology of choice for chromatin mapping studies, yet analysis of these experiments is still in its infancy. Here, we introduce a pipeline for analyzing deep sequencing maps of chromatin structure and apply it to data from S. cerevisiae. We analyze a digestion series where nucleosomes are isolated from under- and overdigested chromatin. We find that certain classes of nucleosomes are unusually susceptible or resistant to overdigestion, with promoter nucleosomes easily digested and mid-coding region nucleosomes being quite stable. We find evidence for highly sensitive nucleosomes located within "nucleosome-free regions," suggesting that these regions are not always completely naked but instead are likely associated with easily digested nucleosomes. Finally, since RNA polymerase is the dominant energy-consuming machine that operates on the chromatin template, we analyze changes in chromatin structure when RNA polymerase is inactivated via a temperature-sensitive mutation. We find evidence that RNA polymerase plays a role in nucleosome eviction at promoters and is also responsible for retrograde shifts in nucleosomes during transcription. Loss of RNA polymerase results in a relaxation of chromatin structure to more closely match in vitro nucleosome positioning preferences. Together, these results provide analytical tools and experimental guidance for nucleosome mapping experiments, and help disentangle the interlinked processes of transcription and chromatin packaging.
Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. ...Here, we combine genome-wide RNA-seq, ChIP-seq, and ATAC-seq to compare the transcriptional and epigenetic identity of small intestinal ILCs, identifying thousands of distinct gene profiles and regulatory elements. Single-cell RNA-seq and flow and mass cytometry analyses reveal compartmentalization of cytokine expression and metabolic activity within the three classical ILC subtypes and highlight transcriptional states beyond the current canonical classification. In addition, using antibiotic intervention and germ-free mice, we characterize the effect of the microbiome on the ILC regulatory landscape and determine the response of ILCs to microbial colonization at the single-cell level. Together, our work characterizes the spectrum of transcriptional identities of small intestinal ILCs and describes how ILCs differentially integrate signals from the microbial microenvironment to generate phenotypic and functional plasticity.
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•Transcriptional and chromatin landscapes of innate lymphoid cells•Functional compartmentalization within ILC subsets revealed by single-cell RNA-seq•Impact of commensal microbiota on epigenetic regulation and gene expression of ILCs•Single-cell analysis of whole-transcriptome responses to microbial colonization
The gut ILC population is a lot more diverse than we thought, and this diversity requires constant signaling from the local microbiota.
Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between ...treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.
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