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1.
Annu Rev Immunol ; 38: 397-419, 2020 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-31990620

RESUMEN

T cell development involves stepwise progression through defined stages that give rise to multiple T cell subtypes, and this is accompanied by the establishment of stage-specific gene expression. Changes in chromatin accessibility and chromatin modifications accompany changes in gene expression during T cell development. Chromatin-modifying enzymes that add or reverse covalent modifications to DNA and histones have a critical role in the dynamic regulation of gene expression throughout T cell development. As each chromatin-modifying enzyme has multiple family members that are typically all coexpressed during T cell development, their function is sometimes revealed only when two related enzymes are concurrently deleted. This work has also revealed that the biological effects of these enzymes often involve regulation of a limited set of targets. The growing diversity in the types and sites of modification, as well as the potential for a single enzyme to catalyze multiple modifications, is also highlighted.


Asunto(s)
Cromatina/genética , Cromatina/metabolismo , Linfopoyesis , Linfocitos T/inmunología , Linfocitos T/metabolismo , Acetilación , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Histonas , Humanos , Linfopoyesis/genética , Linfopoyesis/inmunología , Metilación , Procesamiento Proteico-Postraduccional , Linfocitos T/citología , Linfocitos T/enzimología , Ubiquitinación
2.
Cell ; 187(18): 4824-4826, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39241742

RESUMEN

Epigenetic inheritance of heterochromatin requires transfer of parental H3-H4 tetramers to both daughter duplexes during replication. Three recent papers exploit yeast genetics coupled to inheritance assays and AlphaFold2-multimer predictions coupled to biochemistry to reveal that a replisome component (Mrc1/CLASPIN) is an H3-H4 tetramer chaperone important for parental histone transfer to daughters.


Asunto(s)
Replicación del ADN , Aprendizaje Profundo , Histonas , Saccharomyces cerevisiae , Histonas/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Heterocromatina/metabolismo , Epigénesis Genética
3.
Cell ; 187(18): 5029-5047.e21, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39094569

RESUMEN

The inheritance of parental histones across the replication fork is thought to mediate epigenetic memory. Here, we reveal that fission yeast Mrc1 (CLASPIN in humans) binds H3-H4 tetramers and operates as a central coordinator of symmetric parental histone inheritance. Mrc1 mutants in a key connector domain disrupted segregation of parental histones to the lagging strand comparable to Mcm2 histone-binding mutants. Both mutants showed clonal and asymmetric loss of H3K9me-mediated gene silencing. AlphaFold predicted co-chaperoning of H3-H4 tetramers by Mrc1 and Mcm2, with the Mrc1 connector domain bridging histone and Mcm2 binding. Biochemical and functional analysis validated this model and revealed a duality in Mrc1 function: disabling histone binding in the connector domain disrupted lagging-strand recycling while another histone-binding mutation impaired leading strand recycling. We propose that Mrc1 toggles histones between the lagging and leading strand recycling pathways, in part by intra-replisome co-chaperoning, to ensure epigenetic transmission to both daughter cells.


Asunto(s)
Replicación del ADN , Epigénesis Genética , Histonas , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Histonas/metabolismo , Schizosaccharomyces/metabolismo , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Mutación , Memoria Epigenética
4.
Cell ; 187(10): 2411-2427.e25, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38608704

RESUMEN

We set out to exhaustively characterize the impact of the cis-chromatin environment on prime editing, a precise genome engineering tool. Using a highly sensitive method for mapping the genomic locations of randomly integrated reporters, we discover massive position effects, exemplified by editing efficiencies ranging from ∼0% to 94% for an identical target site and edit. Position effects on prime editing efficiency are well predicted by chromatin marks, e.g., positively by H3K79me2 and negatively by H3K9me3. Next, we developed a multiplex perturbational framework to assess the interaction of trans-acting factors with the cis-chromatin environment on editing outcomes. Applying this framework to DNA repair factors, we identify HLTF as a context-dependent repressor of prime editing. Finally, several lines of evidence suggest that active transcriptional elongation enhances prime editing. Consistent with this, we show we can robustly decrease or increase the efficiency of prime editing by preceding it with CRISPR-mediated silencing or activation, respectively.


Asunto(s)
Sistemas CRISPR-Cas , Cromatina , Epigénesis Genética , Edición Génica , Humanos , Cromatina/metabolismo , Cromatina/genética , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Histonas/metabolismo , Factores de Transcripción/metabolismo , Código de Histonas
5.
Cell ; 187(13): 3262-3283.e23, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38815580

RESUMEN

In eukaryotes, the Suv39 family of proteins tri-methylate lysine 9 of histone H3 (H3K9me) to form constitutive heterochromatin. However, how Suv39 proteins are nucleated at heterochromatin is not fully described. In the fission yeast, current models posit that Argonaute1-associated small RNAs (sRNAs) nucleate the sole H3K9 methyltransferase, Clr4/SUV39H, to centromeres. Here, we show that in the absence of all sRNAs and H3K9me, the Mtl1 and Red1 core (MTREC)/PAXT complex nucleates Clr4/SUV39H at a heterochromatic long noncoding RNA (lncRNA) at which the two H3K9 deacetylases, Sir2 and Clr3, also accumulate by distinct mechanisms. Iterative cycles of H3K9 deacetylation and methylation spread Clr4/SUV39H from the nucleation center in an sRNA-independent manner, generating a basal H3K9me state. This is acted upon by the RNAi machinery to augment and amplify the Clr4/H3K9me signal at centromeres to establish heterochromatin. Overall, our data reveal that lncRNAs and RNA quality control factors can nucleate heterochromatin and function as epigenetic silencers in eukaryotes.


Asunto(s)
Proteínas de Ciclo Celular , Heterocromatina , N-Metiltransferasa de Histona-Lisina , Histonas , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Proteínas de Ciclo Celular/metabolismo , Centrómero/metabolismo , Heterocromatina/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Metilación , Metiltransferasas/metabolismo , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , Schizosaccharomyces/metabolismo , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , ARN de Hongos/genética , ARN Interferente Pequeño/genética
6.
Cell ; 187(18): 5010-5028.e24, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39094570

RESUMEN

Faithful transfer of parental histones to newly replicated daughter DNA strands is critical for inheritance of epigenetic states. Although replication proteins that facilitate parental histone transfer have been identified, how intact histone H3-H4 tetramers travel from the front to the back of the replication fork remains unknown. Here, we use AlphaFold-Multimer structural predictions combined with biochemical and genetic approaches to identify the Mrc1/CLASPIN subunit of the replisome as a histone chaperone. Mrc1 contains a conserved histone-binding domain that forms a brace around the H3-H4 tetramer mimicking nucleosomal DNA and H2A-H2B histones, is required for heterochromatin inheritance, and promotes parental histone recycling during replication. We further identify binding sites for the FACT histone chaperone in Swi1/TIMELESS and DNA polymerase α that are required for heterochromatin inheritance. We propose that Mrc1, in concert with FACT acting as a mobile co-chaperone, coordinates the distribution of parental histones to newly replicated DNA.


Asunto(s)
Replicación del ADN , Epigénesis Genética , Heterocromatina , Histonas , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Histonas/metabolismo , Heterocromatina/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Factores de Elongación Transcripcional/metabolismo , Factores de Elongación Transcripcional/genética , Chaperonas de Histonas/metabolismo , Chaperonas Moleculares/metabolismo , ADN Polimerasa I/metabolismo , ADN Polimerasa I/genética
7.
Cell ; 186(5): 1066-1085.e36, 2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36868209

RESUMEN

A generalizable strategy with programmable site specificity for in situ profiling of histone modifications on unperturbed chromatin remains highly desirable but challenging. We herein developed a single-site-resolved multi-omics (SiTomics) strategy for systematic mapping of dynamic modifications and subsequent profiling of chromatinized proteome and genome defined by specific chromatin acylations in living cells. By leveraging the genetic code expansion strategy, our SiTomics toolkit revealed distinct crotonylation (e.g., H3K56cr) and ß-hydroxybutyrylation (e.g., H3K56bhb) upon short chain fatty acids stimulation and established linkages for chromatin acylation mark-defined proteome, genome, and functions. This led to the identification of GLYR1 as a distinct interacting protein in modulating H3K56cr's gene body localization as well as the discovery of an elevated super-enhancer repertoire underlying bhb-mediated chromatin modulations. SiTomics offers a platform technology for elucidating the "metabolites-modification-regulation" axis, which is widely applicable for multi-omics profiling and functional dissection of modifications beyond acylations and proteins beyond histones.


Asunto(s)
Cromatina , Proteoma , Acilación , Mapeo Cromosómico , Histonas , Supervivencia Celular
8.
Cell ; 186(6): 1162-1178.e20, 2023 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-36931244

RESUMEN

Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.


Asunto(s)
ADN Metiltransferasa 3A , Histonas , Animales , Ratones , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN/genética , Metilasas de Modificación del ADN/genética , Histonas/metabolismo , Enfermedades Neuroinflamatorias
9.
Cell ; 186(19): 4100-4116.e15, 2023 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-37643610

RESUMEN

Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1LSH/HELLS), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1Dnmt1, but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Metilación de ADN , Histonas , Nucleosomas , Ensamble y Desensamble de Cromatina , ADN , Metilasas de Modificación del ADN , Epigénesis Genética , Histonas/genética , Nucleosomas/genética , Semen , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo
10.
Cell ; 186(5): 1050-1065.e19, 2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36750094

RESUMEN

Chromatin landscapes are disrupted during DNA replication and must be restored faithfully to maintain genome regulation and cell identity. The histone H3-H4 modification landscape is restored by parental histone recycling and modification of new histones. How DNA replication impacts on histone H2A-H2B is currently unknown. Here, we measure H2A-H2B modifications and H2A.Z during DNA replication and across the cell cycle using quantitative genomics. We show that H2AK119ub1, H2BK120ub1, and H2A.Z are recycled accurately during DNA replication. Modified H2A-H2B are segregated symmetrically to daughter strands via POLA1 on the lagging strand, but independent of H3-H4 recycling. Post-replication, H2A-H2B modification and variant landscapes are quickly restored, and H2AK119ub1 guides accurate restoration of H3K27me3. This work reveals epigenetic transmission of parental H2A-H2B during DNA replication and identifies cross talk between H3-H4 and H2A-H2B modifications in epigenome propagation. We propose that rapid short-term memory of recycled H2A-H2B modifications facilitates restoration of stable H3-H4 chromatin states.


Asunto(s)
Cromatina , Memoria a Corto Plazo , Ciclo Celular , Replicación del ADN , Histonas/metabolismo , Nucleosomas , Animales , Ratones , Conejos
11.
Cell ; 186(18): 3945-3967.e26, 2023 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-37582358

RESUMEN

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.


Asunto(s)
Neoplasias , Procesamiento Proteico-Postraduccional , Proteómica , Humanos , Acetilación , Histonas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fosforilación , Proteómica/métodos
12.
Annu Rev Biochem ; 90: 287-320, 2021 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-34153213

RESUMEN

The field of epigenetics has exploded over the last two decades, revealing an astonishing level of complexity in the way genetic information is stored and accessed in eukaryotes. This expansion of knowledge, which is very much ongoing, has been made possible by the availability of evermore sensitive and precise molecular tools. This review focuses on the increasingly important role that chemistry plays in this burgeoning field. In an effort to make these contributions more accessible to the nonspecialist, we group available chemical approaches into those that allow the covalent structure of the protein and DNA components of chromatin to be manipulated, those that allow the activity of myriad factors that act on chromatin to be controlled, and those that allow the covalent structure and folding of chromatin to be characterized. The application of these tools is illustrated through a series of case studies that highlight how the molecular precision afforded by chemistry is being used to establish causal biochemical relationships at the heart of epigenetic regulation.


Asunto(s)
Bioquímica/métodos , Técnicas de Química Analítica/métodos , Epigenómica/métodos , Epigenoma , Transferencia Resonante de Energía de Fluorescencia , Heterocromatina/genética , Histonas/metabolismo , Técnicas de Sonda Molecular , Biosíntesis de Proteínas , Factores de Transcripción/genética , Ubiquitinación
13.
Nat Immunol ; 25(9): 1580-1592, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39169234

RESUMEN

Transcriptional condensates play a crucial role in gene expression and regulation, yet their assembly mechanisms remain poorly understood. Here, we report a multi-layered mechanism for condensate assembly by autoimmune regulator (Aire), an essential transcriptional regulator that orchestrates gene expression reprogramming for central T cell tolerance. Aire condensates assemble on enhancers, stimulating local transcriptional activities and connecting disparate inter-chromosomal loci. This functional condensate formation hinges upon the coordination between three Aire domains: polymerization domain caspase activation recruitment domain (CARD), histone-binding domain (first plant homeodomain (PHD1)), and C-terminal tail (CTT). Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly. Conversely, PHD1 binds to the ubiquitous histone mark H3K4me0, keeping Aire dispersed throughout the genome until Aire nucleates on enhancers. Our findings showed that the balance between PHD1-mediated suppression and CTT-mediated stimulation of Aire polymerization is crucial to form transcriptionally active condensates at target sites, providing new insights into controlled polymerization of transcriptional regulators.


Asunto(s)
Proteína AIRE , Factores de Transcripción , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Humanos , Animales , Ratones , Regulación de la Expresión Génica , Elementos de Facilitación Genéticos , Transcripción Genética , Unión Proteica , Histonas/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Factores de Transcripción p300-CBP/genética
14.
Nat Rev Mol Cell Biol ; 25(4): 309-332, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38081975

RESUMEN

The packaging of DNA into chromatin in eukaryotes regulates gene transcription, DNA replication and DNA repair. ATP-dependent chromatin remodelling enzymes (re)arrange nucleosomes at the first level of chromatin organization. Their Snf2-type motor ATPases alter histone-DNA interactions through a common DNA translocation mechanism. Whether remodeller activities mainly catalyse nucleosome dynamics or accurately co-determine nucleosome organization remained unclear. In this Review, we discuss the emerging mechanisms of chromatin remodelling: dynamic remodeller architectures and their interactions, the inner workings of the ATPase cycle, allosteric regulation and pathological dysregulation. Recent mechanistic insights argue for a decisive role of remodellers in the energy-driven self-organization of chromatin, which enables both stability and plasticity of genome regulation - for example, during development and stress. Different remodellers, such as members of the SWI/SNF, ISWI, CHD and INO80 families, process (epi)genetic information through specific mechanisms into distinct functional outputs. Combinatorial assembly of remodellers and their interplay with histone modifications, histone variants, DNA sequence or DNA-bound transcription factors regulate nucleosome mobilization or eviction or histone exchange. Such input-output relationships determine specific nucleosome positions and compositions with distinct DNA accessibilities and mediate differential genome regulation. Finally, remodeller genes are often mutated in diseases characterized by genome dysregulation, notably in cancer, and we discuss their physiological relevance.


Asunto(s)
Cromatina , Histonas , Humanos , Histonas/metabolismo , Nucleosomas , Adenosina Trifosfatasas/metabolismo , Ensamble y Desensamble de Cromatina , ADN , Adenosina Trifosfato/metabolismo
15.
Cell ; 184(16): 4237-4250.e19, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34297924

RESUMEN

The organization of genomic DNA into defined nucleosomes has long been viewed as a hallmark of eukaryotes. This paradigm has been challenged by the identification of "minimalist" histones in archaea and more recently by the discovery of genes that encode fused remote homologs of the four eukaryotic histones in Marseilleviridae, a subfamily of giant viruses that infect amoebae. We demonstrate that viral doublet histones are essential for viral infectivity, localize to cytoplasmic viral factories after virus infection, and ultimately are found in the mature virions. Cryogenic electron microscopy (cryo-EM) structures of viral nucleosome-like particles show strong similarities to eukaryotic nucleosomes despite the limited sequence identify. The unique connectors that link the histone chains contribute to the observed instability of viral nucleosomes, and some histone tails assume structural roles. Our results further expand the range of "organisms" that require nucleosomes and suggest a specialized function of histones in the biology of these unusual viruses.


Asunto(s)
Virus ADN/metabolismo , Histonas/metabolismo , Nucleosomas/metabolismo , Amoeba/virología , Colorantes Fluorescentes/metabolismo , Histonas/química , Modelos Moleculares , Proteómica , Virión/metabolismo
16.
Cell ; 184(2): 352-369.e23, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33357448

RESUMEN

Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.


Asunto(s)
Replicación del ADN/genética , Proteínas F-Box/metabolismo , Neoplasias/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Adulto , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Roturas del ADN de Doble Cadena , Resistencia a Antineoplásicos , Femenino , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad , Interferones/metabolismo , Lisina/metabolismo , Masculino , Metilación , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neoplasias/inmunología , Nucleosomas/metabolismo , Transducción de Señal , Transcripción Genética , Resultado del Tratamiento
17.
Cell ; 184(7): 1775-1789.e19, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33711260

RESUMEN

Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.


Asunto(s)
Linfocitos B/inmunología , Proteínas del Tejido Nervioso/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Autoanticuerpos/inmunología , Autoinmunidad , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas Ligadas a GPI/metabolismo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Histonas/inmunología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo
18.
Cell ; 184(15): 3915-3935.e21, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34174187

RESUMEN

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.


Asunto(s)
Epigenómica , Inmunidad/genética , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Análisis de la Célula Individual , Transcripción Genética , Vacunación , Adolescente , Adulto , Antibacterianos/farmacología , Antígenos CD34/metabolismo , Antivirales/farmacología , Reprogramación Celular , Cromatina/metabolismo , Citocinas/biosíntesis , Combinación de Medicamentos , Femenino , Regulación de la Expresión Génica , Histonas/metabolismo , Humanos , Inmunidad Innata/genética , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Interferón Tipo I/metabolismo , Masculino , Células Mieloides/metabolismo , Polisorbatos/farmacología , Escualeno/farmacología , Receptores Toll-Like/metabolismo , Factor de Transcripción AP-1/metabolismo , Transcriptoma/genética , Adulto Joven , alfa-Tocoferol/farmacología
19.
Cell ; 184(12): 3163-3177.e21, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-33964209

RESUMEN

Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. ELANE attenuates primary tumor growth and produces a CD8+T cell-mediated abscopal effect to attack distant metastases. Porcine pancreatic elastase (ELANE homolog) resists tumor-derived protease inhibitors and exhibits markedly improved therapeutic efficacy. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy.


Asunto(s)
Carcinogénesis/patología , Elastasa de Leucocito/metabolismo , Neoplasias/enzimología , Neoplasias/patología , Regulación Alostérica/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/inmunología , Carcinogénesis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína Catiónica del Eosinófilo/metabolismo , Histonas/metabolismo , Humanos , Ratones , Neoplasias/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Elastasa Pancreática/metabolismo , Inhibidores de Proteasas/farmacología , Dominios Proteicos , Isoformas de Proteínas/metabolismo , Proteolisis/efectos de los fármacos , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Porcinos , Receptor fas/química , Receptor fas/metabolismo
20.
Cell ; 184(16): 4186-4202.e20, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34216540

RESUMEN

Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism is a fundamental process governing the ability of CD4+ helper T cells (TH) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH cell subsets. Polyamines control TH differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus TH cell subset fidelity.


Asunto(s)
Linaje de la Célula , Poliaminas/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromatina/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Colitis/inmunología , Colitis/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Epigenoma , Histonas/metabolismo , Inflamación/inmunología , Inflamación/patología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ornitina Descarboxilasa/metabolismo , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/inmunología , Factores de Transcripción/metabolismo
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