Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.542
Filtrar
Más filtros

Intervalo de año de publicación
1.
Annu Rev Immunol ; 36: 519-548, 2018 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-29394121

RESUMEN

Natural killer (NK) cells have vital functions in human immunity and reproduction. In the innate and adaptive immune responses to infection, particularly by viruses, NK cells respond by secreting inflammatory cytokines and killing infected cells. In reproduction, NK cells are critical for genesis of the placenta, the organ that controls the supply of oxygen and nutrients to the growing fetus. Controlling NK cell functions are interactions of HLA class I with inhibitory NK cell receptors. First evolved was the conserved interaction of HLA-E with CD94:NKG2A; later established were diverse interactions of HLA-A, -B, and -C with killer cell immunoglobulin-like receptors. Characterizing the latter interactions is rapid evolution, which distinguishes human populations and all species of higher primate. Driving this evolution are the different and competing selections imposed by pathogens on NK cell-mediated immunity and by the constraints of human reproduction on NK cell-mediated placentation. Promoting rapid evolution is independent segregation of polymorphic receptors and ligands throughout human populations.


Asunto(s)
Predisposición Genética a la Enfermedad , Inmunidad , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Evolución Biológica , Sitios Genéticos , Genómica/métodos , Haplotipos , Humanos , Complejo Mayor de Histocompatibilidad/genética , Receptores KIR/genética , Receptores KIR/metabolismo
2.
Cell ; 187(19): 5282-5297.e20, 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39168125

RESUMEN

Biomolecular condensates assemble in living cells through phase separation and related phase transitions. An underappreciated feature of these dynamic molecular assemblies is that they form interfaces with other cellular structures, including membranes, cytoskeleton, DNA and RNA, and other membraneless compartments. These interfaces are expected to give rise to capillary forces, but there are few ways of quantifying and harnessing these forces in living cells. Here, we introduce viscoelastic chromatin tethering and organization (VECTOR), which uses light-inducible biomolecular condensates to generate capillary forces at targeted DNA loci. VECTOR can be utilized to programmably reposition genomic loci on a timescale of seconds to minutes, quantitatively revealing local heterogeneity in the viscoelastic material properties of chromatin. These synthetic condensates are built from components that naturally form liquid-like structures in living cells, highlighting the potential role for native condensates to generate forces and do work to reorganize the genome and impact chromatin architecture.


Asunto(s)
Cromatina , ADN , Elasticidad , Cromatina/metabolismo , Cromatina/química , ADN/metabolismo , ADN/química , Humanos , Viscosidad , Condensados Biomoleculares/metabolismo , Condensados Biomoleculares/química , Sitios Genéticos
3.
Cell ; 185(1): 95-112.e18, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34995520

RESUMEN

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.


Asunto(s)
Dermatoglifia , Dedos/crecimiento & desarrollo , Organogénesis/genética , Polimorfismo de Nucleótido Simple , Dedos del Pie/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Pueblo Asiatico/genética , Tipificación del Cuerpo/genética , Niño , Estudios de Cohortes , Femenino , Miembro Anterior/crecimiento & desarrollo , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Proteína del Locus del Complejo MDS1 y EV11/genética , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven
4.
Cell ; 184(12): 3267-3280.e18, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34043941

RESUMEN

Searching for factors to improve knockin efficiency for therapeutic applications, biotechnology, and generation of non-human primate models of disease, we found that the strand exchange protein RAD51 can significantly increase Cas9-mediated homozygous knockin in mouse embryos through an interhomolog repair (IHR) mechanism. IHR is a hallmark of meiosis but only occurs at low frequencies in somatic cells, and its occurrence in zygotes is controversial. Using multiple approaches, we provide evidence for an endogenous IHR mechanism in the early embryo that can be enhanced by RAD51. This process can be harnessed to generate homozygotes from wild-type zygotes using exogenous donors and to convert heterozygous alleles into homozygous alleles without exogenous templates. Furthermore, we identify additional IHR-promoting factors and describe features of IHR events. Together, our findings show conclusive evidence for IHR in mouse embryos and describe an efficient method for enhanced gene conversion.


Asunto(s)
Reparación del ADN/genética , Conversión Génica , Recombinasa Rad51/metabolismo , Alelos , Animales , Secuencia de Bases , Proteína 9 Asociada a CRISPR/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromosomas de los Mamíferos/genética , Roturas del ADN de Doble Cadena , Embrión de Mamíferos , Femenino , Sitios Genéticos , Recombinación Homóloga/genética , Homocigoto , Humanos , Mutación INDEL/genética , Ratones Endogámicos C57BL , Mosaicismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleótido Simple/genética , Ribonucleoproteínas/metabolismo , Cigoto/metabolismo
5.
Cell ; 184(3): 741-758.e17, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33484631

RESUMEN

Both transcription and three-dimensional (3D) architecture of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome structures of single brain cells have not been solved; little is known about the dynamics of single-cell transcriptome and 3D genome after birth. Here, we generated a transcriptome (3,517 cells) and 3D genome (3,646 cells) atlas of the developing mouse cortex and hippocampus by using our high-resolution multiple annealing and looping-based amplification cycles for digital transcriptomics (MALBAC-DT) and diploid chromatin conformation capture (Dip-C) methods and developing multi-omic analysis pipelines. In adults, 3D genome "structure types" delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first post-natal month. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome (chr)-wide differences. These findings uncover an unknown dimension of neurodevelopment.


Asunto(s)
Encéfalo/crecimiento & desarrollo , Genoma , Sensación/genética , Transcripción Genética , Alelos , Animales , Animales Recién Nacidos , Linaje de la Célula/genética , Cromatina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Sitios Genéticos , Impresión Genómica , Ratones , Familia de Multigenes , Neuroglía/metabolismo , Neuronas/metabolismo , Transcriptoma/genética , Corteza Visual/metabolismo
6.
Annu Rev Biochem ; 89: 189-212, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-32208766

RESUMEN

Transcription in several organisms from certain bacteria to humans has been observed to be stochastic in nature: toggling between active and inactive states. Periods of active nascent RNA synthesis known as bursts represent individual gene activation events in which multiple polymerases are initiated. Therefore, bursting is the single locus illustration of both gene activation and repression. Although transcriptional bursting was originally observed decades ago, only recently have technological advances enabled the field to begin elucidating gene regulation at the single-locus level. In this review, we focus on how biochemical, genomic, and single-cell data describe the regulatory steps of transcriptional bursts.


Asunto(s)
Cromatina/química , ADN/genética , Regulación de la Expresión Génica , Genoma , ARN Polimerasa II/genética , ARN Mensajero/genética , Transcripción Genética , Animales , Cromatina/metabolismo , ADN/metabolismo , Células Eucariotas/metabolismo , Sitios Genéticos , Histonas/genética , Histonas/metabolismo , Humanos , Técnicas de Sonda Molecular , Sondas Moleculares/química , ARN Polimerasa II/metabolismo , ARN Mensajero/metabolismo , Análisis de la Célula Individual/métodos , Procesos Estocásticos
7.
Annu Rev Biochem ; 89: 213-234, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-32197056

RESUMEN

Cell-type- and condition-specific profiles of gene expression require coordination between protein-coding gene promoters and cis-regulatory sequences called enhancers. Enhancers can stimulate gene activity at great genomic distances from their targets, raising questions about how enhancers communicate with specific gene promoters and what molecular mechanisms underlie enhancer function. Characterization of enhancer loci has identified the molecular features of active enhancers that accompany the binding of transcription factors and local opening of chromatin. These characteristics include coactivator recruitment, histone modifications, and noncoding RNA transcription. However, it remains unclear which of these features functionally contribute to enhancer activity. Here, we discuss what is known about how enhancers regulate their target genes and how enhancers and promoters communicate. Further, we describe recent data demonstrating many similarities between enhancers and the gene promoters they control, and we highlight unanswered questions in the field, such as the potential roles of transcription at enhancers.


Asunto(s)
Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Genoma , Regiones Promotoras Genéticas , ARN Polimerasa II/genética , Transcripción Genética , Animales , Cromatina/química , Cromatina/metabolismo , ADN/genética , ADN/metabolismo , Células Eucariotas/metabolismo , Sitios Genéticos , Código de Histonas , Histonas/genética , Histonas/metabolismo , Humanos , ARN Polimerasa II/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
8.
Annu Rev Biochem ; 89: 235-253, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-31928411

RESUMEN

Predicting regulatory potential from primary DNA sequences or transcription factor binding patterns is not possible. However, the annotation of the genome by chromatin proteins, histone modifications, and differential compaction is largely sufficient to reveal the locations of genes and their differential activity states. The Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are the central players in this cell type-specific chromatin organization. PcG function was originally viewed as being solely repressive and irreversible, as observed at the homeotic loci in flies and mammals. However, it is now clear that modular and reversible PcG function is essential at most developmental genes. Focusing mainly on recent advances, we review evidence for how PcG and TrxG patterns change dynamically during cell type transitions. The ability to implement cell type-specific transcriptional programming with exquisite fidelity is essential for normal development.


Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Histonas/metabolismo , Proteínas del Grupo Polycomb/genética , Transcripción Genética , Animales , Cromatina/química , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Metilación de ADN , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Embrión de Mamíferos , Embrión no Mamífero , Sitios Genéticos , Histonas/genética , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas del Grupo Polycomb/clasificación , Proteínas del Grupo Polycomb/metabolismo , Elementos de Respuesta , Especificidad de la Especie , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
9.
Cell ; 183(3): 684-701.e14, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-33058756

RESUMEN

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.


Asunto(s)
Enfermedades Metabólicas/genética , MicroARNs/genética , Adipocitos Marrones/patología , Adiposidad , Alelos , Animales , Diferenciación Celular , Línea Celular , Células Cultivadas , Dieta Alta en Grasa , Metabolismo Energético , Epigénesis Genética , Sitios Genéticos , Glucosa/metabolismo , Homeostasis , Humanos , Hipertrofia , Resistencia a la Insulina , Leptina/deficiencia , Leptina/metabolismo , Masculino , Mamíferos/genética , Ratones Endogámicos C57BL , Ratones Obesos , MicroARNs/metabolismo , Obesidad/genética , Oligonucleótidos/metabolismo , Especificidad de la Especie
10.
Cell ; 183(6): 1650-1664.e15, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33125898

RESUMEN

Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos.


Asunto(s)
Alelos , Proteína 9 Asociada a CRISPR/metabolismo , Cromosomas Humanos/genética , Embrión de Mamíferos/metabolismo , Animales , Secuencia de Bases , Blastocisto/metabolismo , Ciclo Celular/genética , Línea Celular , Deleción Cromosómica , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/genética , Implantación del Embrión/genética , Proteínas del Ojo/genética , Fertilización , Edición Génica , Reordenamiento Génico/genética , Sitios Genéticos , Genoma Humano , Genotipo , Heterocigoto , Células Madre Embrionarias Humanas/metabolismo , Humanos , Mutación INDEL/genética , Ratones , Mitosis , Sistemas de Lectura Abierta/genética , Polimorfismo de Nucleótido Simple/genética
11.
Annu Rev Immunol ; 30: 337-56, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22224771

RESUMEN

During an organism's ontogeny and in the adult, each B and T lymphocyte generates a unique antigen receptor, thereby creating the organism's ability to respond to a vast number of different antigens. The antigen receptor loci are organized into distinct regions that contain multiple variable (V), diversity (D), and/or joining (J) and constant (C) coding elements that are scattered across large genomic regions. In this review, we discuss the epigenetic modifications that take place in the different antigen receptor loci, the chromatin structure adopted by the antigen receptor loci to allow recombination of elements separated by large genomic distances, and the relationship between epigenetics and chromatin structure and how they relate to the generation of antigen receptor diversity.


Asunto(s)
Cromatina/química , Receptores de Antígenos/metabolismo , Animales , Epigénesis Genética , Sitios Genéticos , Variación Genética/inmunología , Humanos , Receptores de Antígenos/química , Receptores de Antígenos/genética , Transcripción Genética , Recombinación V(D)J
12.
Cell ; 178(4): 887-900.e14, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31398342

RESUMEN

Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the "polyglutamine disorders."


Asunto(s)
Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Péptidos/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Secuencia de Bases/genética , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Adulto Joven
13.
Cell ; 179(1): 251-267.e24, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31539496

RESUMEN

In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.


Asunto(s)
Neoplasias Encefálicas/genética , Modelos Animales de Enfermedad , Marcación de Gen/métodos , Sitios Genéticos/genética , Glioma/genética , Mutagénesis Insercional/métodos , Transgenes/genética , Animales , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células-Madre Neurales/metabolismo , Recombinasas/metabolismo , Transfección
14.
Cell ; 179(1): 165-179.e18, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31539494

RESUMEN

The three-dimensional organization of chromosomes can have a profound impact on their replication and expression. The chromosomes of higher eukaryotes possess discrete compartments that are characterized by differing transcriptional activities. Contrastingly, most bacterial chromosomes have simpler organization with local domains, the boundaries of which are influenced by gene expression. Numerous studies have revealed that the higher-order architectures of bacterial and eukaryotic chromosomes are dependent on the actions of structural maintenance of chromosomes (SMC) superfamily protein complexes, in particular, the near-universal condensin complex. Intriguingly, however, many archaea, including members of the genus Sulfolobus do not encode canonical condensin. We describe chromosome conformation capture experiments on Sulfolobus species. These reveal the presence of distinct domains along Sulfolobus chromosomes that undergo discrete and specific higher-order interactions, thus defining two compartment types. We observe causal linkages between compartment identity, gene expression, and binding of a hitherto uncharacterized SMC superfamily protein that we term "coalescin."


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas de Archaea/metabolismo , Sulfolobus/citología , Sulfolobus/genética , Adenosina Trifosfatasas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Cromosomas de Archaea/genética , Replicación del ADN/genética , ADN de Archaea/metabolismo , Proteínas de Unión al ADN/metabolismo , Expresión Génica , Sitios Genéticos/genética , Modelos Genéticos , Complejos Multiproteicos/metabolismo , Plásmidos/genética , Unión Proteica/genética , Transcripción Genética
15.
Cell ; 179(6): 1330-1341.e13, 2019 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-31761532

RESUMEN

Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.


Asunto(s)
Cromosomas Humanos/genética , Elementos de Facilitación Genéticos , Amplificación de Genes , Oncogenes , Acetilación , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Cromatina/metabolismo , ADN de Neoplasias/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Genes Relacionados con las Neoplasias , Sitios Genéticos , Glioblastoma/genética , Glioblastoma/patología , Histonas/metabolismo , Humanos , Neuroglía/metabolismo
16.
Cell ; 178(3): 714-730.e22, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31348891

RESUMEN

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.


Asunto(s)
Colitis Ulcerosa/patología , Colon/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Bestrofinas/metabolismo , Antígenos CD8/metabolismo , Estudios de Casos y Controles , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/patología , Enterocitos/citología , Enterocitos/metabolismo , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Factores de Riesgo , Linfocitos T/citología , Linfocitos T/metabolismo , Trombospondinas/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
17.
Cell ; 175(5): 1259-1271.e13, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30454646

RESUMEN

Generally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (Avy) locus, an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class retrotransposed upstream of the agouti coat-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color that is inherited transgenerationally. Here, a systematic genome-wide screen identifies multiple C57BL/6J murine IAPs with Avy epigenetic properties. Each exhibits a stable methylation state within an individual but varies between individuals. Only in rare instances do they act as promoters controlling adjacent gene expression. Their methylation state is locus-specific within an individual, and their flanking regions are enriched for CTCF. Variably methylated IAPs are reprogrammed after fertilization and re-established as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions.


Asunto(s)
Metilación de ADN , Epigénesis Genética , Genes de Partícula A Intracisternal , Inestabilidad Genómica , Proteína de Señalización Agouti/genética , Animales , Sitios de Unión , Factor de Unión a CCCTC/química , Factor de Unión a CCCTC/metabolismo , Sitios Genéticos , Genoma , Herencia , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Retroelementos , Transcripción Genética
18.
Cell ; 173(7): 1705-1715.e16, 2018 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-29906448

RESUMEN

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.


Asunto(s)
Trastorno Bipolar/genética , Estudio de Asociación del Genoma Completo , Esquizofrenia/genética , Trastorno Bipolar/patología , Estudios de Casos y Controles , Sitios Genéticos , Humanos , Herencia Multifactorial/genética , Oportunidad Relativa , Fenotipo , Riesgo , Esquizofrenia/patología , Población Blanca/genética
19.
Cell ; 175(5): 1405-1417.e14, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30318144

RESUMEN

Programmable control of spatial genome organization is a powerful approach for studying how nuclear structure affects gene regulation and cellular function. Here, we develop a versatile CRISPR-genome organization (CRISPR-GO) system that can efficiently control the spatial positioning of genomic loci relative to specific nuclear compartments, including the nuclear periphery, Cajal bodies, and promyelocytic leukemia (PML) bodies. CRISPR-GO is chemically inducible and reversible, enabling interrogation of real-time dynamics of chromatin interactions with nuclear compartments in living cells. Inducible repositioning of genomic loci to the nuclear periphery allows for dissection of mitosis-dependent and -independent relocalization events and also for interrogation of the relationship between gene position and gene expression. CRISPR-GO mediates rapid de novo formation of Cajal bodies at desired chromatin loci and causes significant repression of endogenous gene expression over long distances (30-600 kb). The CRISPR-GO system offers a programmable platform to investigate large-scale spatial genome organization and function.


Asunto(s)
Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Genoma , Ácido Abscísico/farmacología , Línea Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Cuerpos Enrollados/genética , Regulación de la Expresión Génica , Sitios Genéticos , Humanos , Hibridación Fluorescente in Situ , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos
20.
Cell ; 174(2): 433-447.e19, 2018 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-29909985

RESUMEN

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Secuenciación Completa del Genoma , Anciano , Anilidas/uso terapéutico , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Elementos de Facilitación Genéticos/genética , Duplicación de Gen , Reordenamiento Génico , Genes myc , Sitios Genéticos , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/genética , Fenotipo , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA