Abstract 1798: The human mammary circadian transcriptome.

Abstract The circadian rhythm, a phenomenon present in all of Eukaryota and in some members of Prokaryota, describes the processes within an organism that fluctuate throughout a daily cycle. Within peripheral tissues, clock gene expression is organized into a roughly 24-hour period by an elaborate feedback loop mechanism developed around a core set of circadian genes. In addition to maintaining rhythmicity within the molecular clock, key circadian genes such as CLOCK and ARNTL1 are also transcription factors that regulate the expression of a number of additional transcripts; the so-called clock-controlled genes (CCGs). This transcriptional control forms the backbone of circadian rhythmicity and is critical for the maintenance of proper cellular function in a variety of physiological processes, ranging from cell cycle regulation to cellular metabolism. Despite the importance of this regulatory clockwork system, little is known about the extent of molecular circadian control in human peripheral tissues. In fact, the majority of our knowledge of molecular oscillatory systems is derived from studies of model organisms which consistently demonstrate that outside of the core circadian genes; there is virtually no overlap in the compendium of CCGs across tissue types. Based on this critical observation, it is reasonable to expect that if CCGs vary considerably across tissues within the same organism, there may also be considerable heterogeneity across organisms, even within the same tissue type. Here we use next-generation sequencing analyses to provide the first circadian transcriptome in pre-stasis non-immortalized primary human mammary epithelial tissue. Using the non-parametric JTK_CYCLE algorithm, we found that approximately 6% of all expressed genes within this tissue are CCGs. We also find considerable evidence for circadian control in RNA processing events, including splice isoform usage and alternative polyadenylation, and a pathway analysis of all CCGs indicates circadian involvement in multiple signaling and growth pathways. These results demonstrate, for the first time, that a significant and important proportion of the human mammary transcriptome is regulated by the circadian system. Given the importance of circadian disruption in the pathophysiology of a range of human disorders, from metabolic disease to breast cancer, we believe that categorization of the circadian rhythm in human peripheral tissue will lay an important foundation for future breakthroughs in disease prevention, as well as in the development of novel therapeutic strategies. Citation Format: Joseph Combs, Tracy Mandichak, Elizabeth Ferree, Aaron E. Hoffman. The human mammary circadian transcriptome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1798. doi:10.1158/1538-7445.AM2013-1798