RESUMO
Long intergenic non-coding RNAs (LincRNAs) are long RNAs that do not encode proteins. Functional evidence is lacking for most of them. Their biogenesis is not well-known, but it is thought that many lincRNAs originate from genomic duplication of coding material, resulting in pseudogenes, gene copies that lose their original function and can accumulate mutations. While most pseudogenes eventually stop producing a transcript and become erased by mutations, many of these pseudogene-based lincRNAs keep similarity to the parental gene from which they originated, possibly for functional reasons. For example, they can act as decoys for miRNAs targeting the parental gene. Enrichment analysis of function is a powerful tool to discover the functional effects of a treatment producing differential expression of transcripts. However, in the case of lincRNAs, since their function is not easy to define experimentally, such a tool is lacking. To address this problem, we have developed an enrichment analysis tool that focuses on lincRNAs exploiting their functional association, using as a proxy function that of the parental genes and has a focus on human diseases.
Assuntos
Doença/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias da Mama/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Internet , Estimativa de Kaplan-Meier , Prognóstico , RNA Longo não Codificante/metabolismo , Interface Usuário-ComputadorRESUMO
BACKGROUND: NF-κB is widely involved in lymphoid malignancies; however, the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear. METHODS: Using combined ChIP-sequencing and microarray analyses, we determined the cistromes and target gene signatures of canonical and non-canonical NF-κB species in Hodgkin lymphoma (HL) cells. RESULTS: We found that the various NF-κB subunits are recruited to regions with redundant κB motifs in a large number of genes. Yet canonical and non-canonical NF-κB dimers up- and downregulate gene sets that are both distinct and overlapping, and are associated with diverse biological functions. p50 and p52 are formed through NIK-dependent p105 and p100 precursor processing in HL cells and are the predominant DNA binding subunits. Logistic regression analyses of combinations of the p50, p52, RelA, and RelB subunits in binding regions that have been assigned to genes they regulate reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes. These analyses also indicate that the subunit occupancy pattern of NF-κB binding regions and their distance from the genes they regulate are determinants of gene activation versus repression. The pathway-specific signatures of activated and repressed genes distinguish HL from other NF-κB-associated lymphoid malignancies and inversely correlate with gene expression patterns in normal germinal center B cells, which are presumed to be the precursors of HL cells. CONCLUSIONS: We provide insights that are relevant for lymphomas with constitutive NF-κB activation and generally for the decoding of the mechanisms of differential gene regulation through canonical and non-canonical NF-κB signaling.
Assuntos
Estudo de Associação Genômica Ampla , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular , Imunoprecipitação da Cromatina , Biologia Computacional/métodos , Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Motivos de Nucleotídeos , Ligação Proteica , Multimerização Proteica , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/metabolismo , Ativação TranscricionalRESUMO
Pseudogenes have been mainly considered as functionless evolutionary relics since their discovery in 1977. However, multiple mechanisms of pseudogene functionality have been proposed both at the transcriptional and post-transcriptional level. This review focuses on the role of pseudogenes as post-transcriptional regulators. Two lines of research have recently presented strong evidence of their potential function as post-transcriptional regulators of the corresponding parental genes from which they originate. First, pseudogene genomic sequences can encode siRNAs. Second, pseudogene transcripts can act as indirect post-transcriptional regulators decoying ncRNA, in particular miRNAs that target the parental gene. This has been demonstrated for PTEN and KRAS, two genes involved in tumorigenesis. The role of pseudogenes in disease has not been proven and seems to be the next research landmark. In this review, we chronicle the events following the initial discovery of the 'useless' pseudogene to its breakthrough as a functional molecule with hitherto unbeknownst potential to influence human disease.