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1.
Cell ; 187(8): 1955-1970.e23, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38503282

RESUMEN

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.


Asunto(s)
Envejecimiento , Encéfalo , Neuronas , Oligodendroglía , Humanos , Envejecimiento/genética , Envejecimiento/patología , Cromatina/genética , Cromatina/metabolismo , Mutación , Neuronas/metabolismo , Neuronas/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Análisis de Expresión Génica de una Sola Célula , Secuenciación Completa del Genoma , Encéfalo/metabolismo , Encéfalo/patología , Polimorfismo de Nucleótido Simple , Mutación INDEL , Bancos de Muestras Biológicas , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/patología
2.
Cell ; 177(7): 1842-1857.e21, 2019 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-31155235

RESUMEN

Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes.


Asunto(s)
Adenocarcinoma del Pulmón , Reordenamiento Génico , Neoplasias Pulmonares , Mutación , Proteínas de Fusión Oncogénica , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo
3.
Cell ; 173(2): 371-385.e18, 2018 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-29625053

RESUMEN

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.


Asunto(s)
Neoplasias/patología , Algoritmos , Antígeno B7-H1/genética , Biología Computacional , Bases de Datos Genéticas , Entropía , Humanos , Inestabilidad de Microsatélites , Mutación , Neoplasias/genética , Neoplasias/inmunología , Análisis de Componente Principal , Receptor de Muerte Celular Programada 1/genética
4.
Mol Cell ; 83(15): 2624-2640, 2023 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-37419111

RESUMEN

The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets. Integrative computational models based on these data are starting to reveal connections between genome structure and function. We then present a forward-looking perspective and outline current aims to (1) delineate dynamics of nuclear architecture at different timescales, from minutes to weeks as cells differentiate, in populations and in single cells, (2) characterize cis-determinants and trans-modulators of genome organization, (3) test functional consequences of changes in cis- and trans-regulators, and (4) develop predictive models of genome structure and function.


Asunto(s)
Núcleo Celular , Genoma , Genoma/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/metabolismo
5.
Nature ; 618(7967): 1024-1032, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37198482

RESUMEN

Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure1-3 and the evolutionary trajectories4 of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism-which we term translocation-bridge amplification-involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage-fusion-bridge cycle prevalent in some and the translocation-bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.


Asunto(s)
Neoplasias de la Mama , Receptor alfa de Estrógeno , Amplificación de Genes , Oncogenes , Translocación Genética , Femenino , Humanos , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos/metabolismo , Oncogenes/genética , Translocación Genética/genética , Genoma Humano/genética , Roturas del ADN de Doble Cadena , Especificidad de Órganos
6.
Nature ; 619(7971): 828-836, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37438524

RESUMEN

Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.


Asunto(s)
Ataxia Telangiectasia , Empalme del ARN , Niño , Humanos , Ataxia Telangiectasia/tratamiento farmacológico , Ataxia Telangiectasia/genética , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , Estudios Prospectivos , Empalme del ARN/efectos de los fármacos , Empalme del ARN/genética , Secuenciación Completa del Genoma , Intrones , Exones , Medicina de Precisión , Proyectos Piloto
7.
Genes Dev ; 35(9-10): 698-712, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33888559

RESUMEN

Histone chaperones are critical for controlling chromatin integrity during transcription, DNA replication, and DNA repair. Three conserved and essential chaperones, Spt6, Spn1/Iws1, and FACT, associate with elongating RNA polymerase II and interact with each other physically and/or functionally; however, there is little understanding of their individual functions or their relationships with each other. In this study, we selected for suppressors of a temperature-sensitive spt6 mutation that disrupts the Spt6-Spn1 physical interaction and that also causes both transcription and chromatin defects. This selection identified novel mutations in FACT. Surprisingly, suppression by FACT did not restore the Spt6-Spn1 interaction, based on coimmunoprecipitation, ChIP, and mass spectrometry experiments. Furthermore, suppression by FACT bypassed the complete loss of Spn1. Interestingly, the FACT suppressor mutations cluster along the FACT-nucleosome interface, suggesting that they alter FACT-nucleosome interactions. In agreement with this observation, we showed that the spt6 mutation that disrupts the Spt6-Spn1 interaction caused an elevated level of FACT association with chromatin, while the FACT suppressors reduced the level of FACT-chromatin association, thereby restoring a normal Spt6-FACT balance on chromatin. Taken together, these studies reveal previously unknown regulation between histone chaperones that is critical for their essential in vivo functions.


Asunto(s)
Cromatina/metabolismo , Regulación de la Expresión Génica/genética , Chaperonas de Histonas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transcripción Genética/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Chaperonas de Histonas/genética , Mutación , Nucleosomas/genética , Proteínas de Saccharomyces cerevisiae/genética , Factores de Elongación Transcripcional/genética , Factores de Elongación Transcripcional/metabolismo
8.
Nat Rev Genet ; 23(5): 298-314, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34880424

RESUMEN

Distilling biologically meaningful information from cancer genome sequencing data requires comprehensive identification of somatic alterations using rigorous computational methods. As the amount and complexity of sequencing data have increased, so has the number of tools for analysing them. Here, we describe the main steps involved in the bioinformatic analysis of cancer genomes, review key algorithmic developments and highlight popular tools and emerging technologies. These tools include those that identify point mutations, copy number alterations, structural variations and mutational signatures in cancer genomes. We also discuss issues in experimental design, the strengths and limitations of sequencing modalities and methodological challenges for the future.


Asunto(s)
Neoplasias , Mapeo Cromosómico , Biología Computacional , Variaciones en el Número de Copia de ADN , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Neoplasias/genética
9.
Cell ; 155(4): 858-68, 2013 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-24209623

RESUMEN

Microsatellites-simple tandem repeats present at millions of sites in the human genome-can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Inestabilidad de Microsatélites , Epigénesis Genética , Femenino , Mutación del Sistema de Lectura , Estudio de Asociación del Genoma Completo , Humanos , Masculino
10.
Cell ; 155(4): 948-62, 2013 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-24183448

RESUMEN

Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.


Asunto(s)
Algoritmos , Aneuploidia , Genes Supresores de Tumor , Neoplasias/genética , Oncogenes , Dosificación de Gen , Humanos
11.
Cell ; 153(4): 919-29, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23663786

RESUMEN

Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ~20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements.


Asunto(s)
Algoritmos , Genoma Humano , Mutación , Neoplasias/genética , Aberraciones Cromosómicas , Estudio de Asociación del Genoma Completo , Glioblastoma/genética , Humanos , Neoplasias/patología
13.
Cell ; 151(3): 483-96, 2012 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-23101622

RESUMEN

A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain.


Asunto(s)
Núcleo Caudado/citología , Corteza Cerebral/citología , Elementos de Nucleótido Esparcido Largo , Mutación , Neuronas/metabolismo , Análisis de la Célula Individual , Núcleo Caudado/metabolismo , Corteza Cerebral/metabolismo , Niño , Cromosomas Humanos Par 18 , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Mosaicismo , Proteínas Proto-Oncogénicas c-akt/genética , Trisomía
14.
Proc Natl Acad Sci U S A ; 120(51): e2300681120, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38100419

RESUMEN

Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and incontinence. Recently, we reported that heterozygous CWH43 deletions may cause iNPH. Here, we identify mutations affecting nine additional genes (AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, and MYH13) that are statistically enriched among iNPH patients. The encoded proteins are all highly expressed in choroid plexus and ependymal cells, and most have been associated with cilia. Damaging mutations in AK9, which encodes an adenylate kinase, were detected in 9.6% of iNPH patients. Mice homozygous for an iNPH-associated AK9 mutation displayed normal cilia structure and number, but decreased cilia motility and beat frequency, communicating hydrocephalus, and balance impairment. AK9+/- mice displayed normal brain development and behavior until early adulthood, but subsequently developed communicating hydrocephalus. Together, our findings suggest that heterozygous mutations that impair ventricular epithelial function may contribute to iNPH.


Asunto(s)
Adenilato Quinasa , Hidrocéfalo Normotenso , Hidrocefalia , Adulto , Animales , Humanos , Ratones , Persona de Mediana Edad , Encéfalo , Plexo Coroideo , Hidrocefalia/genética , Hidrocéfalo Normotenso/genética , Hidrocéfalo Normotenso/complicaciones , Mutación , Proteínas , Adenilato Quinasa/genética , Adenilato Quinasa/metabolismo
15.
Cell ; 140(1): 99-110, 2010 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-20085705

RESUMEN

Polycomb group (PcG) proteins are essential for accurate axial body patterning during embryonic development. PcG-mediated repression is conserved in metazoans and is targeted in Drosophila by Polycomb response elements (PREs). However, targeting sequences in humans have not been described. While analyzing chromatin architecture in the context of human embryonic stem cell (hESC) differentiation, we discovered a 1.8kb region between HOXD11 and HOXD12 (D11.12) that is associated with PcG proteins, becomes nuclease hypersensitive, and then shows alteration in nuclease sensitivity as hESCs differentiate. The D11.12 element repressed luciferase expression from a reporter construct and full repression required a highly conserved region and YY1 binding sites. Furthermore, repression was dependent on the PcG proteins BMI1 and EED and a YY1-interacting partner, RYBP. We conclude that D11.12 is a Polycomb-dependent regulatory region with similarities to Drosophila PREs, indicating conservation in the mechanisms that target PcG function in mammals and flies.


Asunto(s)
Células Madre Embrionarias/metabolismo , Genes Homeobox/genética , Proteínas de Homeodominio/genética , Elementos Reguladores de la Transcripción , Proteínas Represoras/metabolismo , Diferenciación Celular , Cromatina/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteínas Nucleares/metabolismo , Complejo Represivo Polycomb 1 , Proteínas del Grupo Polycomb , Proteínas Proto-Oncogénicas/metabolismo
16.
Mol Cell ; 66(1): 77-88.e5, 2017 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-28366642

RESUMEN

Spt5 is an essential and conserved factor that functions in transcription and co-transcriptional processes. However, many aspects of the requirement for Spt5 in transcription are poorly understood. We have analyzed the consequences of Spt5 depletion in Schizosaccharomyces pombe using four genome-wide approaches. Our results demonstrate that Spt5 is crucial for a normal rate of RNA synthesis and distribution of RNAPII over transcription units. In the absence of Spt5, RNAPII localization changes dramatically, with reduced levels and a relative accumulation over the first ∼500 bp, suggesting that Spt5 is required for transcription past a barrier. Spt5 depletion also results in widespread antisense transcription initiating within this barrier region. Deletions of this region alter the distribution of RNAPII on the sense strand, suggesting that the barrier observed after Spt5 depletion is normally a site at which Spt5 stimulates elongation. Our results reveal a global requirement for Spt5 in transcription elongation.


Asunto(s)
Proteínas Cromosómicas no Histona/metabolismo , ARN sin Sentido/biosíntesis , ARN de Hongos/biosíntesis , ARN Mensajero/biosíntesis , Saccharomyces cerevisiae/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/metabolismo , Elongación de la Transcripción Genética , Factores de Elongación Transcripcional/metabolismo , Proteínas Cromosómicas no Histona/genética , Biología Computacional , Bases de Datos Genéticas , Regulación Fúngica de la Expresión Génica , Genoma Fúngico , Genotipo , Mutación , Fenotipo , Regiones Promotoras Genéticas , ARN Polimerasa II/metabolismo , Empalme del ARN , ARN sin Sentido/genética , ARN de Hongos/genética , ARN Mensajero/genética , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Factores de Tiempo , Factores de Elongación Transcripcional/genética
17.
Nucleic Acids Res ; 51(21): 11453-11465, 2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-37823611

RESUMEN

SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions have been less well studied compared to other mobile element insertions. Here, we identified polymorphic SVA insertions from 3646 whole-genome sequencing (WGS) samples of >150 diverse populations and constructed a polymorphic SVA insertion reference catalog. Using 20 long-read samples, we also assembled reference and polymorphic SVA sequences and characterized the internal hexamer/variable-number-tandem-repeat (VNTR) expansions as well as differing SVA activity for SVA subfamilies and human populations. In addition, we developed a module to annotate both reference and polymorphic SVA copies. By characterizing the landscape of both reference and polymorphic SVA retrotransposons, our study enables more accurate genotyping of these elements and facilitate the discovery of pathogenic SVA insertions.


Asunto(s)
Genoma Humano , Retroelementos , Humanos , Elementos Alu , Genoma Humano/genética , Repeticiones de Minisatélite/genética , Retroelementos/genética , Elementos de Nucleótido Esparcido Corto
18.
Genes Dev ; 31(19): 1988-2002, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-29070704

RESUMEN

Regulatory decisions in Drosophila require Polycomb group (PcG) proteins to maintain the silent state and Trithorax group (TrxG) proteins to oppose silencing. Since PcG and TrxG are ubiquitous and lack apparent sequence specificity, a long-standing model is that targeting occurs via protein interactions; for instance, between repressors and PcG proteins. Instead, we found that Pc-repressive complex 1 (PRC1) purifies with coactivators Fs(1)h [female sterile (1) homeotic] and Enok/Br140 during embryogenesis. Fs(1)h is a TrxG member and the ortholog of BRD4, a bromodomain protein that binds to acetylated histones and is a key transcriptional coactivator in mammals. Enok and Br140, another bromodomain protein, are orthologous to subunits of a mammalian MOZ/MORF acetyltransferase complex. Here we confirm PRC1-Br140 and PRC1-Fs(1)h interactions and identify their genomic binding sites. PRC1-Br140 bind developmental genes in fly embryos, with analogous co-occupancy of PRC1 and a Br140 ortholog, BRD1, at bivalent loci in human embryonic stem (ES) cells. We propose that identification of PRC1-Br140 "bivalent complexes" in fly embryos supports and extends the bivalency model posited in mammalian cells, in which the coexistence of H3K4me3 and H3K27me3 at developmental promoters represents a poised transcriptional state. We further speculate that local competition between acetylation and deacetylation may play a critical role in the resolution of bivalent protein complexes during development.


Asunto(s)
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriología , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Genes del Desarrollo/genética , Complejo Represivo Polycomb 1/metabolismo , Acetilación , Animales , Sitios de Unión , Diferenciación Celular , Células Cultivadas , Drosophila melanogaster/citología , Embrión no Mamífero , Silenciador del Gen , Células Madre Embrionarias Humanas , Humanos , Complejos Multiproteicos/metabolismo , Unión Proteica
19.
Prostate ; 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39252459

RESUMEN

BACKGROUND: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi. METHODS: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes). RESULTS: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10-7). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070). CONCLUSIONS: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation.

20.
Development ; 148(9)2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33929509

RESUMEN

The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.


Asunto(s)
Disección , Factor Nuclear 6 del Hepatocito/metabolismo , Factores de Transcripción Otx/metabolismo , Retina/crecimiento & desarrollo , Células Fotorreceptoras Retinianas Conos/metabolismo , Factores de Transcripción/metabolismo , Animales , Sitios de Unión , Pollos , Cromatina , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Factor Nuclear 6 del Hepatocito/genética , Factores de Transcripción Otx/genética , Retina/metabolismo , Células Madre
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