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1.
Nat Genet ; 50(10): 1375-1380, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224643

RESUMO

Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations1-6. cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas7,8. We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification1. This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology.


Assuntos
Transformação Celular Neoplásica/genética , Cromossomos Humanos/química , Códon sem Sentido , Neoplasias Colorretais/genética , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Células CACO-2 , Neoplasias Colorretais/epidemiologia , DNA de Neoplasias/química , Bases de Dados Genéticas , Frequência do Gene , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Células K562 , Células MCF-7 , Conformação de Ácido Nucleico , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Células Tumorais Cultivadas
2.
Blood ; 132(19): 2040-2052, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30194254

RESUMO

To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.


Assuntos
Centro Germinativo/patologia , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Polimorfismo de Nucleotídeo Único , Linfócitos T/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Código das Histonas , Doença de Hodgkin/imunologia , Humanos , Imunidade , NF-kappa B/genética , NF-kappa B/imunologia , Regiões Promotoras Genéticas , Linfócitos T/imunologia , Linfócitos T/metabolismo
3.
Nat Commun ; 9(1): 554, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396438

RESUMO

The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'.

4.
Nat Genet ; 50(2): 259-269, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29358650

RESUMO

Pioneer transcription factors establish new cell-fate competence by triggering chromatin remodeling. However, many features of pioneer action, such as their kinetics and stability, remain poorly defined. Here, we show that Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. Pax7 binds its targeted enhancers rapidly, but chromatin remodeling and gene activation are slower. Enhancers opened by Pax7 show a loss of DNA methylation and acquire stable epigenetic memory, as evidenced by binding of nonpioneer factors after Pax7 withdrawal. This work shows that transient Pax7 expression is sufficient for stable specification of cell identity.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula/genética , Elementos Facilitadores Genéticos , Fator de Transcrição PAX7/metabolismo , Animais , Células Cultivadas , Metilação de DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes de Troca , Instabilidade Genômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos/genética , Ligação Proteica
5.
Nat Commun ; 9(1): 67, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29302025

RESUMO

To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.


Assuntos
Proteínas de Transporte/genética , Epistasia Genética , Erros Inatos do Metabolismo/genética , Mutação , Peroxirredoxinas/genética , Vitamina B 12/metabolismo , Alelos , Azacitidina/farmacologia , Sequência de Bases , Inibidores Enzimáticos/farmacologia , Saúde da Família , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Heterozigoto , Humanos , Masculino , Erros Inatos do Metabolismo/metabolismo , Oxirredutases , Linhagem , Sequenciamento Completo do Genoma
6.
Cell Rep ; 20(11): 2556-2564, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28903037

RESUMO

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.


Assuntos
Cromossomos Humanos Par 5/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Elongação da Transcrição/genética , Alelos , Diploide , Epigênese Genética , Epigenômica , Loci Gênicos , Humanos , Proteínas Nucleares/metabolismo , Mapeamento Físico do Cromossomo , Prognóstico , Ligação Proteica , Fatores de Risco , Elongação da Transcrição Genética , Resposta a Proteínas não Dobradas/genética
7.
DNA Cell Biol ; 32(6): 310-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23672204

RESUMO

We have previously shown that ceramide, a proapoptotic molecule decreases in the mouse heart as it adapts to hypoxia. We have also shown that its precursor, dihydroceramide, accumulates with hypoxia. This implicates the enzyme dihydroceramide desaturase (DHC-DS), which converts dihydroceramide to ceramide, in a potential regulatory checkpoint in cardiomyocytes. We hypothesised that the regulation of de novo ceramide synthesis plays an important role in the cardiomyocyte adaptation to hypoxia. We used an established mouse model to induce acute and chronic hypoxia. Cardiac tissues were extracted and quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of DHC-DS. Electrophoretic Mobility Shift Assays (EMSAs) and qRT-PCR were used to evaluate the activity and expression levels of an array of transcription factors that might regulate DEGS1 gene expression. We demonstrated that DEGS1 mRNA levels decrease with time in hypoxic mice concurrent with the decrease in HAND2 transcripts. Interestingly, the DEGS1 promoter harbors overlapping sites for Hand2 and Nuclear Factor of Activated T-cells (NFATC) transcription factors. We have demonstrated a physical interaction between NFATC1 and the E-Box proteins with EMSA and coimmunoprecipitation assays. The regulation of de novo ceramide synthesis in response to hypoxia and this newly described interaction between E-box and NFATC transcription factors will pave the way to identify new pathways in the adaptation of the cardiomyocyte to stress. The elucidation of these pathways will in the long-term provide insights into potential targets for novel therapeutic regimens.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ceramidas/biossíntese , Hipóxia/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Fatores de Transcrição NFATC/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sítios de Ligação , Linhagem Celular , Ceramidas/metabolismo , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Ventrículos do Coração/metabolismo , Humanos , Camundongos , Fatores de Transcrição NFATC/genética , Regiões Promotoras Genéticas
8.
Ann Med ; 44(7): 680-93, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21923612

RESUMO

The heart as a functional organ first appeared in bilaterians as a single peristaltic pump and evolved through arthropods, fish, amphibians, and finally mammals into a four-chambered engine controlling blood-flow within the body. The acquisition of cardiac complexity in the evolving heart was a product of gene duplication events and the co-option of novel signaling pathways to an ancestral cardiac-specific gene network. T-box factors belong to an evolutionary conserved family of transcriptional regulators with diverse roles in development. Their regulatory functions are integral in the initiation and potentiation of heart development, and mutations in these genes are associated with congenital heart defects. In this review we will discuss the evolutionary conserved cardiac regulatory functions of this family as well as their implication in disease in an aim to facilitate future gene-targeted and regenerative therapeutic remedies.


Assuntos
Evolução Biológica , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Coração/embriologia , Coração/crescimento & desenvolvimento , Miocárdio/metabolismo , Proteínas com Domínio T/metabolismo , Animais , Sistema de Condução Cardíaco/embriologia , Sistema de Condução Cardíaco/fisiologia , Cardiopatias Congênitas/genética , Humanos
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