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Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

ABSTRACT: Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

PROVIDER: PRJNA1066383 | ENA |

REPOSITORIES: ENA

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Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

Project description:Transcription factors (TFs) control gene expression by interacting with DNA and cofactors to regulate transcription. Human TF genes produce multiple protein isoforms with altered DNA binding domains, effector domains, and other protein regions. The global extent to which this results in functional differences between TF isoforms of the same gene remains unknown. Here, we systematically tested 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Compared to the reference isoform, two-thirds of alternative TF isoforms exhibit differences in their molecular activities, which often cannot be predicted from sequence alone. We observed two primary categories of alternative TF isoforms: “rewirers” and “negative regulators”, both of which are associated with differentiation and cancer. Our results support a model wherein the relative expression levels of and interactions between TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.

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Translation initiation site profiling reveals widespread synthesis of non-AUG-initiated protein isoforms in yeast

Project description:Genomic analyses in budding yeast have helped to define the foundational principles of eukaryotic gene expression, but have systematically excluded specific classes of potential coding regions, including those with non-AUG start codons. Without methods to define coding regions empirically, the prevalence of these non-canonical coding regions has been impossible to assess. Here, we applied an experimental approach to globally annotate translation initiation sites in yeast and identified a class of 149 genes that encode N-terminally extended alternate protein isoforms that result from translation initiation at non-AUG codons upstream of the annotated AUG start codon. These alternate isoforms are produced in concert with canonical isoforms and are translated with a high degree of specificity, resulting from initiation at only a small subset of possible start codons in 5’ leader regions. Their translation is enriched during meiosis, and is induced by low eIF5A levels, which are observed in this context. These findings reveal widespread production of non-canonical protein isoforms and, more generally, show unexpected complexity to the rules by which the budding yeast genome is decoded.

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Extensive structural differences of closely related 3’ mRNA isoforms: links to Pab1 binding and mRNA stability

Project description:Alternative polyadenylation generates numerous 3' mRNA isoforms per gene; regulation of this process is critical in development and impaired in cancer. Individual isoforms from the same gene can vary greatly in biological properties such as translational efficiency, localization, and half-life. Even closely related isoforms - including those differing by a single nt - can have different biological properties, but the underlying mechanisms are unknown. Here we show that many highly similar yeast isoforms unexpectedly exhibit extensive structural variation and differential Pab1 binding, and that these physical properties serve as a good predictor of relative isoform stability. We developed DREADS, a dimethyl sulphate (DMS)-based technique, to obtain the first transcriptome-scale structural description of individual 3' mRNA isoforms in vivo. Strikingly, near-identical yeast mRNA isoforms arising from the same gene can possess dramatically different DMS modification profiles over hundreds of nt upstream of the poly(A) tail. DREADS analyses of the same mRNAs refolded in vitro or in different species indicate that structural differences in vivo are often due to trans- acting factors. CLIP-READS, a technique we developed to measure isoform-specific binding, reveals that differences in Poly(A) binding protein (Pab1) binding to 3' ends correlate with the extent of structural variation for closely-spaced isoforms. A pattern encompassing single-strandedness near the 3' terminus, double-stranded character of the poly(A) tail, and low Pab1 binding is significantly associated with mRNA stability. Sequences responsible for isoform-specific structures, differential Pab1 binding, and mRNA stability are evolutionarily conserved, and are indicative of biological function.

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