Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Immunity ; 57(5): 1005-1018.e7, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38697116

RESUMEN

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.


Asunto(s)
Factor de Unión a CCCTC , Diferenciación Celular , Interferón gamma , Interleucina-22 , Interleucinas , Células TH1 , Animales , Factor de Unión a CCCTC/metabolismo , Factor de Unión a CCCTC/genética , Células TH1/inmunología , Ratones , Diferenciación Celular/inmunología , Interferón gamma/metabolismo , Sitios de Unión , Interleucinas/metabolismo , Interleucinas/genética , Elementos de Facilitación Genéticos/genética , Ratones Endogámicos C57BL , Cromatina/metabolismo , Toxoplasmosis/inmunología , Toxoplasmosis/parasitología , Toxoplasmosis/genética , Regulación de la Expresión Génica , Toxoplasma/inmunología , Citocinas/metabolismo , Linaje de la Célula , Células Th17/inmunología
2.
Cell ; 173(5): 1165-1178.e20, 2018 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-29706548

RESUMEN

Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.


Asunto(s)
Adenosina Trifosfato/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Genoma , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Línea Celular , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Cromosomas/metabolismo , Proteínas de Unión al ADN , Humanos , Ratones , Mutagénesis , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Cohesinas
3.
Cell ; 170(3): 507-521.e18, 2017 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-28735753

RESUMEN

In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT.


Asunto(s)
Fragilidad Cromosómica , Roturas del ADN de Doble Cadena , Neoplasias/genética , Animales , Linfocitos B/metabolismo , Factor de Unión a CCCTC , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas Represoras/metabolismo
4.
Cell ; 162(5): 1051-65, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26300125

RESUMEN

Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.


Asunto(s)
Cromatina/metabolismo , Cromosomas Humanos/metabolismo , Proyecto Genoma Humano , Línea Celular , Cromosomas Humanos/química , Estudios de Cohortes , Femenino , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Histonas/metabolismo , Humanos , Linfocitos/metabolismo , Masculino , Sitios de Carácter Cuantitativo , Elementos Reguladores de la Transcripción
6.
Mol Cell ; 75(6): 1229-1242.e5, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31377117

RESUMEN

Interferon gamma (IFN-γ), critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired Ifng response, and compromised host defense. Insertion of a polyA signal ablated the Ifng-as1 full-length transcript and impaired host defense, while allowing proper chromatin structure. Transient knockdown of Ifng-as1 also reduced IFN-γ production. In humans, discordant expression of IFNG and IFNG-AS1 was evident in memory T cells, with high expression of this long non-coding RNA (lncRNA) and low expression of the cytokine. These results establish Ifng-as1 as an important regulator of Ifng expression, as a DNA element and transcribed RNA, involved in dynamic and cell state-specific responses to infection.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Memoria Inmunológica , Infecciones/inmunología , Interferón gamma/inmunología , ARN no Traducido/inmunología , Linfocitos T/inmunología , Animales , Cromatina/genética , Cromatina/inmunología , Femenino , Técnicas de Silenciamiento del Gen , Infecciones/genética , Infecciones/patología , Interferón gamma/genética , Ratones , ARN no Traducido/genética , Linfocitos T/patología
7.
Mol Cell ; 72(4): 636-649.e8, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30293785

RESUMEN

Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3'RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3'RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3'RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3' Igh super-enhancer.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Cambio de Clase de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/genética , Proteínas Supresoras de Tumor/genética , Animales , Linfocitos B , Línea Celular , Cromatina/genética , Cromatina/metabolismo , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , ADN/genética , Elementos de Facilitación Genéticos , Reordenamiento Génico , Humanos , Dominios MYND , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Secuencias Reguladoras de Ácidos Nucleicos , Hipermutación Somática de Inmunoglobulina/genética , Proteínas Supresoras de Tumor/metabolismo
8.
Mol Cell ; 67(4): 566-578.e10, 2017 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-28803781

RESUMEN

50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells.


Asunto(s)
Linfocitos B/metabolismo , Ciclo Celular , Núcleo Celular/metabolismo , Ensamble y Desensamble de Cromatina , Cromatina/metabolismo , Histonas/metabolismo , Activación de Linfocitos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Acetilcoenzima A/metabolismo , Acetilación , Adenosina Trifosfato/metabolismo , Animales , Linfocitos B/inmunología , Línea Celular , Cromatina/química , Cromatina/genética , Metilación de ADN , Epigénesis Genética , Genotipo , Histonas/química , Inmunidad Humoral , Metilación , Ratones Endogámicos C57BL , Ratones Noqueados , Conformación de Ácido Nucleico , Fenotipo , Dominios y Motivos de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-myc/química , Proteínas Proto-Oncogénicas c-myc/genética , Imagen Individual de Molécula , Relación Estructura-Actividad , Factores de Tiempo , Transcripción Genética
9.
EMBO Rep ; 23(9): e55146, 2022 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-35993175

RESUMEN

CCCTC-binding factor (CTCF) is an eleven zinc finger (ZF), multivalent transcriptional regulator, that recognizes numerous motifs thanks to the deployment of distinct combinations of its ZFs. The great majority of the ~50,000 genomic locations bound by the CTCF protein in a given cell type is intergenic, and a fraction of these sites overlaps with transcriptional enhancers. Furthermore, a proportion of the regions bound by CTCF intersect genes and promoters. This suggests multiple ways in which CTCF may impact gene expression. At promoters, CTCF can directly affect transcription. At more distal sites, CTCF may orchestrate interactions between regulatory elements and help separate eu- and heterochromatic areas in the genome, exerting a chromatin barrier function. In this review, we outline how CTCF contributes to the regulation of the three-dimensional structure of chromatin and the formation of chromatin domains. We discuss how CTCF binding and architectural functions are regulated. We examine the literature implicating CTCF in controlling gene expression in development and disease both by acting as an insulator and a factor facilitating regulatory elements to efficiently interact with each other in the nuclear space.


Asunto(s)
Cromatina , Proteínas Represoras , Sitios de Unión , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Cromatina/genética , Elementos de Facilitación Genéticos , Expresión Génica , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
10.
Nature ; 551(7678): 51-56, 2017 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-29094699

RESUMEN

Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Posicionamiento de Cromosoma , Animales , Cromatina/química , Cromatina/genética , Elementos de Facilitación Genéticos/genética , Epigénesis Genética , Hígado/metabolismo , Ratones , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Cohesinas
11.
J Immunol ; 194(7): 3432-43, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25732733

RESUMEN

V(D)J recombination assembles Ag receptor genes during lymphocyte development. Enhancers at AR loci are known to control V(D)J recombination at associated alleles, in part by increasing chromatin accessibility of the locus, to allow the recombination machinery to gain access to its chromosomal substrates. However, whether there is a specific mechanism to induce chromatin accessibility at AR loci is still unclear. In this article, we highlight a specialized epigenetic marking characterized by high and extended H3K4me3 levels throughout the Dß-Jß-Cß gene segments. We show that extended H3K4 trimethylation at the Tcrb locus depends on RNA polymerase II (Pol II)-mediated transcription. Furthermore, we found that the genomic regions encompassing the two DJCß clusters are highly enriched for Ser(5)-phosphorylated Pol II and short-RNA transcripts, two hallmarks of transcription initiation and early transcription. Of interest, these features are shared with few other tissue-specific genes. We propose that the entire DJCß regions behave as transcription "initiation" platforms, therefore linking a specialized mechanism of Pol II transcription with extended H3K4 trimethylation and highly accessible Dß and Jß gene segments.


Asunto(s)
Cromatina/genética , Sitios Genéticos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Transcripción Genética , Animales , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Inmunoprecipitación de Cromatina , Metilación de ADN , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento , Histonas/metabolismo , Ratones , Ratones Noqueados , Modelos Biológicos , ARN Polimerasa II/metabolismo , Recombinación V(D)J
12.
Mol Syst Biol ; 11(6): 812, 2015 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-26040288

RESUMEN

Cell-to-cell variability in gene expression is important for many processes in biology, including embryonic development and stem cell homeostasis. While heterogeneity of gene expression levels has been extensively studied, less attention has been paid to mRNA polyadenylation isoform choice. 3' untranslated regions regulate mRNA fate, and their choice is tightly controlled during development, but how 3' isoform usage varies within genetically and developmentally homogeneous cell populations has not been explored. Here, we perform genome-wide quantification of polyadenylation site usage in single mouse embryonic and neural stem cells using a novel single-cell transcriptomic method, BATSeq. By applying BATBayes, a statistical framework for analyzing single-cell isoform data, we find that while the developmental state of the cell globally determines isoform usage, single cells from the same state differ in the choice of isoforms. Notably this variation exceeds random selection with equal preference in all cells, a finding that was confirmed by RNA FISH data. Variability in 3' isoform choice has potential implications on functional cell-to-cell heterogeneity as well as utility in resolving cell populations.


Asunto(s)
Diferenciación Celular/genética , Células-Madre Neurales , Poliadenilación/genética , ARN Mensajero/biosíntesis , Animales , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Heterogeneidad Genética , Ratones , Isoformas de Proteínas/genética , Señales de Poliadenilación de ARN 3'/genética , Estabilidad del ARN/genética , ARN Mensajero/genética , Análisis de la Célula Individual
13.
EMBO J ; 30(20): 4198-210, 2011 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-21847099

RESUMEN

Combinations of post-translational histone modifications shape the chromatin landscape during cell development in eukaryotes. However, little is known about the modifications exactly delineating functionally engaged regulatory elements. For example, although histone H3 lysine 4 mono-methylation (H3K4me1) indicates the presence of transcriptional gene enhancers, it does not provide clearcut information about their actual position and stage-specific activity. Histone marks were, therefore, studied here at genomic loci differentially expressed in early stages of T-lymphocyte development. The concomitant presence of the three H3K4 methylation states (H3K4me1/2/3) was found to clearly reflect the activity of bona fide T-cell gene enhancers. Globally, gain or loss of H3K4me2/3 at distal genomic regions correlated with, respectively, the induction or the repression of associated genes during T-cell development. In the Tcrb gene enhancer, the H3K4me3-to-H3K4me1 ratio decreases with the enhancer's strength. Lastly, enhancer association of RNA-polymerase II (Pol II) correlated with the presence of H3K4me3 and Pol II accumulation resulted in local increase of H3K4me3. Our results suggest the existence of functional links between Pol II occupancy, H3K4me3 enrichment and enhancer activity.


Asunto(s)
Elementos de Facilitación Genéticos , Epigénesis Genética , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Histonas/metabolismo , Animales , Complejo CD3/inmunología , Línea Celular , Activación de Linfocitos/genética , Lisina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Polimerasa II/metabolismo , Linfocitos T/metabolismo , Timo/crecimiento & desarrollo , Timo/metabolismo
14.
Semin Immunol ; 22(6): 330-6, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20829066

RESUMEN

V(D)J recombination assembles antigen receptor genes from germline V, D and J segments during lymphocyte development. In αßT-cells, this leads to the subsequent expression of T-cell receptor (TCR) ß and α chains. Generally, V(D)J recombination is closely controlled at various levels, including cell-type and cell-stage specificities, order of locus/gene segment recombination, and allele usage to mediate allelic exclusion. Many of these controls rely on the modulation of gene accessibility to the recombination machinery, involving not only biochemical changes in chromatin arrangement and structural modifications of chromosomal organization and positioning, but also the refined composition of the recombinase targets, the so-called recombination signal sequences. Here, we summarize current knowledge regarding the regulation of V(D)J recombination at the Tcrb gene locus, certainly one for which these various levels of control and regulatory components have been most extensively investigated.


Asunto(s)
Epigenómica , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Recombinación Genética , Linfocitos T/metabolismo , Alelos , Animales , Humanos
15.
Sci Adv ; 10(32): eadl4893, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39121214

RESUMEN

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion of MED26 had the most profound impact on the entire gene regulatory network, acting downstream of chromatin spatial architecture and without affecting TATA box-binding protein (TBP) recruitment. These results indicate that later steps in the initiation of transcriptional bursts are primary nodes for integrating gene networks in single cells.


Asunto(s)
Proteínas de Ciclo Celular , Cromatina , Redes Reguladoras de Genes , Factores de Transcripción , Transcripción Genética , Cromatina/metabolismo , Cromatina/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Humanos , Regulación de la Expresión Génica , Complejo Mediador/metabolismo , Complejo Mediador/genética , Análisis de la Célula Individual , Transcriptoma , Cohesinas , Proteínas que Contienen Bromodominio
16.
Genome Res ; 20(11): 1493-502, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20841431

RESUMEN

Characterization of the epigenetic landscape fundamentally contributes toward deciphering the regulatory mechanisms that govern gene expression. However, despite an increasing flow of newly generated data, no clear pattern of chromatin modifications has so far been linked to specific modes of transcriptional regulation. Here, we used high-throughput genomic data from CD4(+) T lymphocytes to provide a comprehensive analysis of histone H3 lysine 4 dimethylation (H3K4me2) enrichment in genomic regions surrounding transcriptional start sites (TSSs). We discovered that a subgroup of genes linked to T cell functions displayed high levels of H3K4me2 within their gene body, in sharp contrast to the TSS-centered profile typical of housekeeping genes. Analysis of additional chromatin modifications and DNase I hypersensitive sites (DHSS) revealed a combinatorial chromatin signature characteristic of this subgroup. We propose that this epigenetic feature reflects the activity of an as yet unrecognized, intragenic cis-regulatory platform dedicated to refining tissue-specificity in gene expression.


Asunto(s)
Regulación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Ensamble y Desensamble de Cromatina/genética , Inmunoprecipitación de Cromatina/métodos , Análisis por Conglomerados , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Histona Metiltransferasas , Humanos , Lisina/metabolismo , Masculino , Metaboloma , Ratones , Especificidad de Órganos/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética
17.
Front Genet ; 13: 1009390, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36479251

RESUMEN

The unique qualities of the human brain are a product of a complex evolutionary process. Evolution, famously described by François Jacob as a "tinkerer," builds upon existing genetic elements by modifying and repurposing them for new functions. Genetic changes in DNA may lead to the emergence of new genes or cause altered gene expression patterns. Both gene and regulatory element mutations may lead to new functions. Yet, this process may lead to side-effects. An evolutionary trade-off occurs when an otherwise beneficial change, which is important for evolutionary success and is under strong positive selection, concurrently results in a detrimental change in another trait. Pleiotropy occurs when a gene affects multiple traits. Antagonistic pleiotropy is a phenomenon whereby a genetic variant leads to an increase in fitness at one life-stage or in a specific environment, but simultaneously decreases fitness in another respect. Therefore, it is conceivable that the molecular underpinnings of evolution of highly complex traits, including brain size or cognitive ability, under certain conditions could result in deleterious effects, which would increase the susceptibility to psychiatric or neurodevelopmental diseases. Here, we discuss possible trade-offs and antagonistic pleiotropies between evolutionary change in a gene sequence, dosage or activity and the susceptibility of individuals to autism spectrum disorders and schizophrenia. We present current knowledge about genes and alterations in gene regulatory landscapes, which have likely played a role in establishing human-specific traits and have been implicated in those diseases.

18.
Ann N Y Acad Sci ; 1518(1): 120-130, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36285711

RESUMEN

The evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed of electrically excitable neuronal networks connected by chemical synapses and nonexcitable glial cells that provide for homeostasis and defense. The evolution of neuroglia began with the emergence of the centralized nervous system and proceeded through a continuous increase in their complexity. In the primate brain, especially in the brain of humans, the astrocyte lineage is exceedingly complex, with the emergence of new types of astroglial cells possibly involved in interlayer communication and integration.


Asunto(s)
Astrocitos , Neuroglía , Humanos , Animales , Neuroglía/fisiología , Astrocitos/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Encéfalo/fisiología , Oligodendroglía/fisiología
19.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-34451862

RESUMEN

Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals' lives. NDs have complex etiologies but commonly feature altered gene expression and dysfunctions of the essential chromatin-modifying factors. Hence, compounds that target DNA and histone modification pathways, the so-called epidrugs, constitute promising tools to treat NDs. Yet, targeting the entire epigenome might reveal insufficient to modify a chosen gene expression or even unnecessary and detrimental to the patients' health. New technologies hold a promise to expand the clinical toolkit in the fight against NDs. (Epi)genome engineering using designer nucleases, including CRISPR-Cas9 and TALENs, can potentially help restore the correct gene expression patterns by targeting a defined gene or pathway, both genetically and epigenetically, with minimal off-target activity. Here, we review the implication of epigenetic machinery in NDs. We outline syndromes caused by mutations in chromatin-modifying enzymes and discuss the functional consequences of mutations in regulatory DNA in NDs. We review the approaches that allow modifying the (epi)genome, including tools based on TALENs and CRISPR-Cas9 technologies, and we highlight how these new strategies could potentially change clinical practices in the treatment of NDs.

20.
Cell Syst ; 7(5): 482-495.e10, 2018 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-30414923

RESUMEN

The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.


Asunto(s)
Factor de Unión a CCCTC/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Células-Madre Neurales/metabolismo , Animales , Diferenciación Celular , Cromatina/ultraestructura , Ratones , Células Madre Embrionarias de Ratones/fisiología , Células Madre Embrionarias de Ratones/ultraestructura , Células-Madre Neurales/fisiología , Células-Madre Neurales/ultraestructura , Unión Proteica , Cohesinas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA