- B.S., Animal Science, Tarleton State University, May 2012
Entered program in 2012
My research investigates the molecular mechanisms underlying rhythmic gene expression in the mouse. As most organisms, mouse exhibits 24-hr rhythms in their biochemistry, physiology and behavior. These circadian (for circa diem, about a day) rhythms are cell-autonomous and generated by the molecular circadian clock. Because dysfunctional circadian clock contributes to a wide range of diseases such as obesity, diabetes, and neuropsychiatric disorders, further characterization of the molecular components of the circadian clock will facilitate and strengthen the ability to restore circadian rhythms and to prevent or treat circadian diseases.
The mammalian circadian clock relies on transcriptional-translational feedback loops which regulate the rhythmic expression of approximately ~10-15% of cellular transcripts expressed in mouse liver (Koike et al., 2012; Menet et al., 2012; Panda et al., 2002). The two major positive transcription factors CLOCK and BMAL1 sit at the apex of the clock and bind to e-boxes to initiate the transcription of clock-controlled genes. Recently, a disconnect has been described between CLOCK:BMAL1 binding to DNA and the transcriptional output of their target genes, suggesting that CLOCK:BMAL1 use novel modalities to regulate circadian clock controlled genes’ expression. One such modality appears to involve CLOCK:BMAL1-mediated rhythmic chromatin opening, in which CLOCK:BMAL1 directly controls the temporal regulation of its target genes’ chromatin environment and only indirectly impacts their transcriptional activation (Menet et al., 2014). My thesis project seeks to determine the molecular mechanisms through which CLOCK:BMAL1 promote rhythmic chromatin remodeling and how this remodeling regulates transcriptional output. My hypothesis is that rhythmic binding of CLOCK:BMAL1 to the DNA recruits chromatin remodelers to a transcriptionally permissive chromatin landscape and initiates the binding of other transcription factors that prime target genes for transcription.
Broader Impacts of Research Project:
Circadian rhythms are interrelated biological processes that drive the cyclic nature of metabolism, physiology and behavior. These rhythms are apparent in daily changes in blood pressure and body temperature, circadian hormone secretion, sleep-wake cycles, feeding-fasting cycles, motor activity and different levels of alertness. Evidence indicates that disruptions of the circadian clock have a devastating influence on many physiological functions, which ultimately leads to the development of many pathologies. My research seeks to characterize the molecular mechanisms underlying the generation of circadian rhythms in the mouse. My work is expected to provide new avenues to study why clock dysfunction contributes to the development of pathologies.