Linking Core Promoter Classes to Circadian Transcription

Abstract

Abstract Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs), is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription. Author Summary Circadian rhythms switch gene expression on and off with a daily rhythm in most tissues in mammals and other animals. Typically, thousands of genes are affected, and the functions of these rhythms include preparing and adjusting various physiological functions in tissues to meet time-of-day dependent requirements optimally. The controllers of the rhythms are often transcription factors (proteins which regulate transcription), which are relatively well known. However, there is a layer between transcription factor action and transcriptional activity whose role in circadian transcription has not previously been characterized: the core promoter. The core promoter acts as a template for the assembly of the intricate machinery that governs initiation of transcription. There are different types of core promoters that are typically used for different types of genes. It is not known which types of core promoters are used for the rhythmically induced genes. Here, it is shown that there are specific characteristics of core promoters driving rhythmic transcription in mice and flies. Furthermore, it is shown that there is a class of strong circadian promoters in mice that drive strong rhythms with very intense average transcriptional rates. These results help understanding the regulatory systems governing circadian transcription, and ultimately, aid the understanding of many diseases resulting from disturbed circadian rhythms.