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Cancer Cell Jul 2022T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed...
T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to systematically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of the INO80 and BAF chromatin remodeling complexes improved T cell persistence in tumors. In vivo Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chromatin accessibility and led to improved antitumor immunity. In summary, we provide an atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of epigenetic state can improve T cell responses in cancer immunotherapy.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; Epigenomics; Humans; Mice; Neoplasms; T-Lymphocytes
PubMed: 35750052
DOI: 10.1016/j.ccell.2022.06.001 -
Trends in Neurosciences Sep 2018Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of... (Review)
Review
Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.
Topics: Aging; Animals; Chromatin; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Histones; Humans; Models, Biological; Molecular Targeted Therapy; Neurodegenerative Diseases
PubMed: 29885742
DOI: 10.1016/j.tins.2018.05.005 -
Neuroscience and Biobehavioral Reviews Sep 2013Physical activity, and specifically exercise, has been suggested as a potential treatment for drug addiction. In this review, we discuss clinical and preclinical... (Review)
Review
Physical activity, and specifically exercise, has been suggested as a potential treatment for drug addiction. In this review, we discuss clinical and preclinical evidence for the efficacy of exercise at different phases of the addiction process. Potential neurobiological mechanisms are also discussed focusing on interactions with dopaminergic and glutamatergic signaling and chromatin remodeling in the reward pathway. While exercise generally produces an efficacious response, certain exercise conditions may be either ineffective or lead to detrimental effects depending on the level/type/timing of exercise exposure, the stage of addiction, the drug involved, and the subject population. During drug use initiation and withdrawal, its efficacy may be related to its ability to facilitate dopaminergic transmission, and once addiction develops, its efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. We conclude with future directions, including the development of exercise-based interventions alone or as an adjunct to other strategies for treating drug addiction.
Topics: Brain; Brain-Derived Neurotrophic Factor; Chromatin Assembly and Disassembly; Dopamine; Exercise; Exercise Therapy; Humans; Substance-Related Disorders
PubMed: 23806439
DOI: 10.1016/j.neubiorev.2013.06.011 -
Glia Aug 2020Oligodendrocytes, the myelinating cells in the vertebrate central nervous system, produce myelin sheaths to enable saltatory propagation of action potentials. The... (Review)
Review
Oligodendrocytes, the myelinating cells in the vertebrate central nervous system, produce myelin sheaths to enable saltatory propagation of action potentials. The process of oligodendrocyte myelination entails a stepwise progression from precursor specification to differentiation, which is coordinated by a series of transcriptional and chromatin remodeling events. ATP-dependent chromatin remodeling enzymes, which utilize ATP as an energy source to control chromatin dynamics and regulate the accessibility of chromatin to transcriptional regulators, are critical for oligodendrocyte lineage development and regeneration. In this review, we focus on the latest insights into the spatial and temporal specificity of chromatin remodelers during oligodendrocyte development, myelinogenesis, and regeneration. We will also bring together various plausible mechanisms by which lineage specific transcriptional regulators coordinate with chromatin remodeling factors for programming genomic landscapes to specifically modulate these different processes during developmental myelination and remyelination upon injury.
Topics: Animals; Cell Differentiation; Central Nervous System; Chromatin Assembly and Disassembly; Humans; Myelin Sheath; Oligodendroglia; Remyelination
PubMed: 32460418
DOI: 10.1002/glia.23837 -
Frontiers in Endocrinology 2021The mechanisms of epigenetic gene regulation-histone modifications, chromatin remodeling, DNA methylation, and noncoding RNA-use metabolites as enzymatic cofactors and... (Review)
Review
The mechanisms of epigenetic gene regulation-histone modifications, chromatin remodeling, DNA methylation, and noncoding RNA-use metabolites as enzymatic cofactors and substrates in reactions that allow chromatin formation, nucleotide biogenesis, transcription, RNA processing, and translation. Gene expression responds to demands from cellular processes that use specific metabolites and alters or maintains cellular metabolic status. However, the roles of metabolites-particularly nucleotides-as regulatory molecules in epigenetic regulation and biological processes remain largely unknown. Here we review the crosstalk between gene expression, nucleotide metabolism, and cellular processes, and explore the role of metabolism in epigenetics as a critical regulator of biological events.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Gene Expression; Histones; Humans; Nucleotides; Protein Processing, Post-Translational
PubMed: 34526971
DOI: 10.3389/fendo.2021.731648 -
Experimental & Molecular Medicine Jan 2017Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are... (Review)
Review
Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.
Topics: Acetylation; Animals; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Histones; Humans; Learning; Memory; Methylation; Protein Processing, Post-Translational; Signal Transduction
PubMed: 28082740
DOI: 10.1038/emm.2016.140 -
Cancer Metastasis Reviews Jun 2023The ATP-dependent chromatin remodeling complex SWI/SNF (also called BAF) is critical for the regulation of gene expression. During the evolution from yeast to mammals,... (Review)
Review
The ATP-dependent chromatin remodeling complex SWI/SNF (also called BAF) is critical for the regulation of gene expression. During the evolution from yeast to mammals, the BAF complex has evolved an enormous complexity that contains a high number of subunits encoded by various genes. Emerging studies highlight the frequent involvement of altered mammalian SWI/SNF chromatin-remodeling complexes in human cancers. Here, we discuss the recent advances in determining the structure of SWI/SNF complexes, highlight the mechanisms by which mutations affecting these complexes promote cancer, and describe the promising emerging opportunities for targeted therapies.
Topics: Animals; Humans; Transcription Factors; Neoplasms; Mutation; Chromatin Assembly and Disassembly; Mammals
PubMed: 37093326
DOI: 10.1007/s10555-023-10102-5 -
Genes Jan 2019The near complete replacement of somatic chromatin in spermatids is, perhaps, the most striking nuclear event known to the eukaryotic domain. The process is far from... (Review)
Review
The near complete replacement of somatic chromatin in spermatids is, perhaps, the most striking nuclear event known to the eukaryotic domain. The process is far from being fully understood, but research has nevertheless unraveled its complexity as an expression of histone variants and post-translational modifications that must be finely orchestrated to promote the DNA topological change and compaction provided by the deposition of protamines. That this major transition may not be genetically inert came from early observations that transient DNA strand breaks were detected in situ at chromatin remodeling steps. The potential for genetic instability was later emphasized by our demonstration that a significant number of DNA double-strand breaks (DSBs) are formed and then repaired in the haploid context of spermatids. The detection of DNA breaks by 3'OH end labeling in the whole population of spermatids suggests that a reversible enzymatic process is involved, which differs from canonical apoptosis. We have set the stage for a better characterization of the genetic impact of this transition by showing that post-meiotic DNA fragmentation is conserved from human to yeast, and by providing tools for the initial mapping of the genome-wide DSB distribution in the mouse model. Hence, the molecular mechanism of post-meiotic DSB formation and repair in spermatids may prove to be a significant component of the well-known male mutation bias. Based on our recent observations and a survey of the literature, we propose that the chromatin remodeling in spermatids offers a proper context for the induction of de novo polymorphism and structural variations that can be transmitted to the next generation.
Topics: Animals; Chromatin Assembly and Disassembly; Chromosomal Instability; Male; Mutation Rate; Spermatids; Spermatogenesis
PubMed: 30646585
DOI: 10.3390/genes10010040 -
Experimental Cell Research Oct 2022Skeletal muscle development and regeneration is governed by the combined action of Myf5, MyoD, Mrf4 and MyoG, also known as the myogenic regulatory factors (MRFs). These... (Review)
Review
Skeletal muscle development and regeneration is governed by the combined action of Myf5, MyoD, Mrf4 and MyoG, also known as the myogenic regulatory factors (MRFs). These transcription factors are expressed in a highly spatio-temporal restricted manner, ensuring the significant functional and metabolic diversity observed between the different muscle groups. In this review, we will discuss the multiple layers of regulation that contribute to the control of the exquisite expression patterns of the MRFs in particular, and of myogenic genes in general. We will highlight all major regulatory processes that play a role in myogenesis: from those that modulate chromatin status and transcription competence, such as DNA methylation, histone modification, chromatin remodeling, or non-coding RNAs, to those that control transcript and protein processing and modification, such as alternative splicing, polyadenylation, other mRNA modifications, or post-translational protein modifications. All these processes are exquisitely and tightly coordinated to ensure the proper activation, maintenance and termination of the myogenic process.
Topics: Chromatin Assembly and Disassembly; Gene Expression; Gene Expression Regulation; Muscle Development; Muscle, Skeletal; Myogenic Regulatory Factors; Transcription Factors
PubMed: 35926660
DOI: 10.1016/j.yexcr.2022.113299 -
Current Oncology (Toronto, Ont.) Dec 2022Multiple myeloma (MM) is a complex disease driven by numerous genetic and epigenetic alterations that are acquired over time. Despite recent progress in the... (Review)
Review
Multiple myeloma (MM) is a complex disease driven by numerous genetic and epigenetic alterations that are acquired over time. Despite recent progress in the understanding of MM pathobiology and the availability of innovative drugs, which have pronounced clinical outcome, this malignancy eventually progresses to a drug-resistant lethal stage and, thus, novel therapeutic drugs/models always play an important role in effective management of MM. Modulation of tumor microenvironment is one of the hallmarks of cancer biology, including MM, which affects the myeloma genomic architecture and disease progression subtly through chromatin modifications. The bone marrow niche has a prime role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the ecosystem between multiple myeloma bone marrow microenvironment and chromatin remodeling. Extensive gene expression profile analysis has indeed provided the framework for new risk stratification of MM patients and identifying novel molecular targets and therapeutics. However, key tumor microenvironment factors/immune cells and their interactions with chromatin remodeling complex proteins that drive MM cell growth and progression remain grossly undefined.
Topics: Humans; Multiple Myeloma; Tumor Microenvironment; Chromatin Assembly and Disassembly; Ecosystem; Bone Marrow
PubMed: 36547163
DOI: 10.3390/curroncol29120749