University of Pittsburgh

In addition to the circadian rhythms (rhythms with a period of ~24h), biological rhythms with a period of ~12h also exist. Dr. Zhu’s lab recently discovered a cell-autonomous mammalian 12h-clock that runs independently from the circadian clock to regulate 12h oscillations of gene expression and metabolism. The majority of these 12h oscillations peaks at dawn and dusk and is independent from the BMAL1-regulated circadian clock. Instead, they depend on the unfolded protein response transcription factor XBP1. Liver-specific deletion of XBP1s globally impairs the murine 12h transcriptome, but not the circadian rhythms in vivo. XBP1s-dependent 12h-transcriptome is enriched for genes involved in transcription regulation, mRNA processing, ribosome biogenesis, translation initiation, protein processing in the endoplasmic reticulum (ER) and protein sorting in ER/Golgi in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). Up-regulation of these pathways at dawn and dusk may allow for elevated rates of mRNA and protein processing and trafficking occurring at transition periods between fasting/feeding and rest/activity, to cope with increased metabolic stress during these times. In addition to liver, prevalent 12h transcriptome are also found in other peripheral tissues including skeletal muscle, brown and white adipose tissue, heart and lung in both rodent and primates. These 12h rhythms of gene expression are cell-autonomous and can be entrained by stress and metabolic cues. Furthermore, mammalian 12h rhythms are highly conserved evolutionarily and hypothesized to evolve from the 12h circatidal clock from certain marine animals.

Dr. Zhu’s lab is currently investigating the regulation as well as the physiological/pathological functions of the 12h-clock, taking a combination of computational, biochemical, genetic, cellular, imaging and genomic approaches. Specific areas of the study are 1) developing sensitive and robust 12h-clock reporter systems using CRISPR-CAS9 based imaging approaches, 2) to determine the transcriptional and post-transcriptional regulatory network of 12h-clock control combining transcriptome, cistrome and epigenome profiling with innovative computational analysis, 3) to determine how the 12h-clock regulates the metabolism dynamics and how cellular metabolism feeds back to influence the 12h rhythms of gene expression through epigenetic and other mechanisms; 4) to identify non-cell autonomous regulators/factors of 12h clock and protein quality control, and 5) to establish the causal relationships between the disruption of a 12h-clock with progression to aging-related metabolic diseases and the aging process as a whole, with the ultimate goal to successfully translate the these knowledge into chronotherapy-based medicine and disease prevention.