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1.
J Mol Biol ; 431(6): 1088-1097, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30690030

RESUMO

We show here that the specific use of fast or slowly translated codons in the early coding region of a gene may influence both the mRNA stability and premature transcription termination. We first inserted a pair of nearly identical 42-base-pair (bp)-long sequences into codon 3 of the Escherichia coli lacZ gene. The only difference between the two inserts was that the first base in one was moved to become the last base in the other, providing a difference in the reading frame, one of which had the biased codons typical for ribosomal protein genes and which previously was shown to be faster translated than average. This insert reduced the mRNA stability and increased premature transcription termination and together resulted in a hundred-fold difference in lacZ expression. We next generated lacZ variants with 7, 14 or 21 fast translated, ribosomal-type codons inserted into codon 13 of lacZ. This gave progressively more unstable mRNAs and also progressively increased transcription termination up to 90%. By modeling, based on estimates of the translation rate of individual codons, we can explain these observations by an increased susceptibility of the mRNA to degradation, determined by the length and degree of the early mRNA being uncovered by ribosomes. Thus, we suggest that the translation rate differences among the synonymous codons early in a gene enable a "velocity code" within the amino acid coding ability, where the translation rate differences encode the mRNA stability and the premature termination of the RNA polymerase.


Assuntos
Escherichia coli/genética , RNA Bacteriano/genética , RNA Mensageiro/genética , Códon , Regulação Bacteriana da Expressão Gênica , Óperon Lac , Biossíntese de Proteínas , Estabilidade de RNA , Transcrição Gênica
2.
Nat Commun ; 9(1): 1661, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695774

RESUMO

Inflammatory bowel disease (IBD) is a chronic intestinal disorder, with two main types: Crohn's disease (CD) and ulcerative colitis (UC), whose molecular pathology is not well understood. The majority of IBD-associated SNPs are located in non-coding regions and are hard to characterize since regulatory regions in IBD are not known. Here we profile transcription start sites (TSSs) and enhancers in the descending colon of 94 IBD patients and controls. IBD-upregulated promoters and enhancers are highly enriched for IBD-associated SNPs and are bound by the same transcription factors. IBD-specific TSSs are associated to genes with roles in both inflammatory cascades and gut epithelia while TSSs distinguishing UC and CD are associated to gut epithelia functions. We find that as few as 35 TSSs can distinguish active CD, UC, and controls with 85% accuracy in an independent cohort. Our data constitute a foundation for understanding the molecular pathology, gene regulation, and genetics of IBD.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Sequências Reguladoras de Ácido Nucleico/genética , Adulto , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/patologia , Colonoscopia , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Regulação para Cima
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