Optimized Analysis of DNA Methylation and Gene Expression from Small, Anatomically-defined Areas of the Brain

Exposure to diet, drugs and early life adversity during sensitive windows of life 1,2 can lead to lasting changes in gene expression that contribute to ...

Max Planck Institute of Psychiatry

Alternative splicing serves to increase biological diversity and adaptation. Many genes, including the glucocorticoid receptor (GR), contain multiple 5'-untranslated exons in their promoter regions that can give rise to various mRNA isoforms encoding the same protein. To date, information on the mouse GR promoter remains sparse. Here, we extensively characterize alternative first exons of the mouse GR to reveal homology to the rat and human. We further find that, although most promoters are broadly expressed in various tissues, transcription of individual promoters can be differentially regulated by growth factor- and depolarization-induced signaling. Moreover, in addition to selective promoter usage, the alternative first exon transcripts differentially control RNA stability and translation efficiency, indicative of their role in GR expression. In conclusion, the composite GR promoter enables multilayered adjustments in gene expression through transcriptional and posttranscriptional mechanisms that may serve varying physiological demands.

Differential regulation and function of 5'-untranslated GR-exon 1 transcripts.

&Eacute;pissage alternatif sert &agrave; augmenter la diversit&eacute; biologique et adaptation. Plusieurs g&egrave;nes, y compris le r&eacute;cepteur des glucocortico&iuml;des (GR), contiennent plusieurs exons non traduite de 5&#39; dans leurs r&eacute;gions promotrices qui peuvent donner lieu &agrave; diverses isoformes d&#39;ARNm codant pour la prot&eacute;ine m&ecirc;me. &Agrave; ce jour, les informations sur la souris promoteur GR reste clairsem&eacute;e. Ici, nous caract&eacute;risons intensivement les exons premi&egrave;res alternatives de la souris GR pour r&eacute;v&eacute;ler l&#39;homologie au rat et humaine. Plus loin, nous trouvons que, transcription de divers promoteurs peut &ecirc;tre r&eacute;glement&eacute;e par le facteur de croissance-d&eacute;polarisation induite et signalisation bien que la plupart des promoteurs sont largement exprim&eacute;es dans divers tissus, diff&eacute;remment. En outre, en plus de l&#39;utilisation du promoteur s&eacute;lectif, les transcriptions d&#39;exon premi&egrave;res alternative diff&eacute;rentiellement contr&ocirc;lent l&#39;efficacit&eacute; stabilit&eacute; et traduction RNA, indicative de leur r&ocirc;le dans l&#39;expression de GR. En conclusion, le promoteur GR composite permet des ajustements par multicouches dans l&#39;expression des g&egrave;nes par le biais de transcriptionnelles et post-transcriptionnelle des m&eacute;canismes qui peuvent servir &agrave; diverses exigences physiologiques.

R&eacute;gulation diff&eacute;rentielle et fonction de transcriptions de GR-exon 1 non traduite de 5&#39;.

Splicing alternativo serve per aumentare la diversit&agrave; biologica e adattamento. Molti geni, tra cui i recettori glucocorticoidi (GR), contengono pi&ugrave; esoni 5&#39;-non tradotta nelle loro regioni promotore che possono dare origine a diverse isoforme di mRNA codifica per la proteina stessa. Fino ad oggi, informazioni sul mouse promotore GR rimane scarsa. Qui, abbiamo ampiamente caratterizzano esoni alternativi primi del mouse GR per rivelare omologia di ratto e umani. Troviamo inoltre che, anche se la maggior parte dei promotori sono largamente espressi nei vari tessuti, trascrizione dei singoli promotori differenziale regolabile da fattore di crescita - e depolarizzazione indotta di segnalazione. Inoltre, oltre all&#39;utilizzo del promotore selettiva, le trascrizioni di esone alternativo prime controllano differenzialmente RNA traduzione di stabilit&agrave; e di efficienza, indicativo del loro ruolo nell&#39;espressione GR. In conclusione, il promotore GR composito consente multistrati regolazioni nell&#39;espressione genica attraverso meccanismi trascrizionali e posttranscriptional che possono servire diverse esigenze fisiologiche.

Arleta Kuczynska

Max Planck Institute of Psychiatry

Optimized Analysis of DNA Methylation and Gene Expression from Small, Anatomically-defined Areas of the Brain