Transcriptional Regulation of INSR, the Insulin Receptor Gene

The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease.

Critical role of deadenylation in regulating poly(A) rhythms and circadian gene expression

The mammalian circadian clock is deeply rooted in rhythmic regulation of gene expression. Rhythmic transcriptional control mediated by the circadian transcription factors is thought to be the main driver of mammalian circadian gene expression. However, mounting evidence has demonstrated the importance of rhythmic post-transcriptional controls, and it remains unclear how the transcriptional and post-transcriptional mechanisms collectively control rhythmic gene expression. A recent study discovered rhythmicity in poly(A) tail length in mouse liver and its strong correlation with protein expression rhythms. To understand the role of rhythmic poly(A) regulation in circadian gene expression, we constructed a parsimonious model that depicts rhythmic control imposed upon basic mRNA expression and poly(A) regulation processes, including transcription, deadenylation, polyadenylation, and degradation. The model results reveal the rhythmicity in deadenylation as the strongest contributor to the rhythmicity in poly(A) tail length and the rhythmicity in the abundance of the mRNA subpopulation with long poly(A) tails (a rough proxy for mRNA translatability). In line with this finding, the model further shows that the experimentally observed distinct peak phases in the expression of deadenylases, regardless of other rhythmic controls, can robustly group the rhythmic mRNAs by their peak phases in poly(A) tail length and in abundance of the subpopulation with long poly(A) tails. This provides a potential mechanism to synchronize the phases of target gene expression regulated by the same deadenylases. Our findings highlight the critical role of rhythmic deadenylation in regulating poly(A) rhythms and circadian gene expression.Author SummaryThe biological circadian clock regulates various bodily functions such that they anticipate and respond to the day-and-night cycle. To achieve this, the circadian clock controls rhythmic gene expression, and these genes ultimately drive the rhythmicity of downstream biological processes. As a mechanism of driving circadian gene expression, rhythmic transcriptional control has attracted the central focus. However, mounting evidence has also demonstrated the importance of rhythmic post-transcriptional controls. Here we use mathematical modeling to investigate how transcriptional and post-transcriptional rhythms coordinately control rhythmic gene expression. We have particularly focused on rhythmic regulation of the length of poly(A) tail, a nearly universal feature of mRNAs that controls mRNA stability and translation. Our model reveals that the rhythmicity of deadenylation, the process that shortens the poly(A) tail, is the dominant contributor to the rhythmicity in poly(A) tail length and mRNA translatability. Particularly, the phase of deadenylation nearly overrides the other rhythmic processes in controlling the phases of poly(A) tail length and mRNA translatability. Our finding highlights the critical role of rhythmic deadenylation in circadian gene expression control.

Regulation of entry into gametogenesis by Ste11: the endless game

Sexual reproduction is a fundamental aspect of eukaryotic cells, and a conserved feature of gametogenesis is its dependency on a master regulator. The ste11 gene was isolated more than 20 years ago by the Yamamoto laboratory as a suppressor of the uncontrolled meiosis driven by a pat1 mutant. Numerous studies from this laboratory and others have established the role of the Ste11 transcription factor as the master regulator of the switch between proliferation and differentiation in fission yeast. The transcriptional and post-transcriptional controls of ste11 expression are intricate, but most are not redundant. Whereas the transcriptional controls ensure that the gene is transcribed at a high level only when nutrients are rare, the post-transcriptional controls restrict the ability of Ste11 to function as a transcription factor to the G1-phase of the cell cycle from where the differentiation programme is initiated. Several feedback loops ensure that the cell fate decision is irreversible. The complete panel of molecular mechanisms operating to warrant the timely expression of the ste11 gene and its encoded protein basically mirrors the advances in the understanding of the numerous ways by which gene expression can be modulated.