Ph.D., Mayo Graduate School, 2003
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Genomic and envrionmental factors in the development of obesity, metabolic syndrome and Type 2 diabetes
Researcher ID: D-6341-2011
Genome and the environment factors in the development of obesity, metabolic syndrome and Type 2 diabetes
The overarching goal of my laboratory is to understand how the genome and the environment interact with one another and the role this interaction plays in human health in general, and in the development of obesity, metabolic syndrome and Type 2 diabetes in particular. Towards this end I aim to: (1) dissect the genetic programs involved in the maintenance of energy homeostasis of adult, post-differentiated tissues; (2) understand the molecular mechanisms of the circadian oscillator; and (3) elucidate how the circadian oscillator and energy metabolism interact with one another and become dysregulated in obesity and disease.
According to the Centers for Disease Control and Prevention, the rate of obesity in the United States has doubled since 1990. Today, over sixty percent of the U.S. population is overweight and 30% of adults are categorized as obese, with 50% of the population expected to fall within this latter category within twenty years. By that time, the costs of obesity and associated ailments - including cancer, cardiovascular disease and metabolic disorders - will exceed 14% of the national health care expenditure (>800 billion USD). In fact, type II diabetes is the fastest growing non-communicable disease in the U.S., with 8-11% of the total U.S. population currently diagnosed as diabetic while metabolic syndrome affects a quarter of adults. Thus, there is a compelling need to understand the causes for this dramatic increase in excess body weight and the mechanisms that underlie its associated pathologies.
The circadian system is an endogenous timing mechanism that is present across phyla and is responsible for synchronizing an organism's behavior and physiology to the most optimal time of day. In mammals, this system is based on a subcellular transcription-translation circuit which generates strong, ~24-hour oscillations in up to 20% of the transcriptome of any given organ. Thus, the impact of this system is far-reaching, exerting considerable influence and control over most, if not all, major organismal processes. Importantly, the circadian oscillator has emerged as a critical orchestrator of metabolism and energy homeostasis, from the cellular to the organismal levels. Circadian stress due to environmental factors, such as those commonly found in modern lifestyles (jet lag, shift work, artificially-extended photoperiod) has been linked epidemiologically to a number of disease processes, including fertility problems, cancer, weight gain and metabolic syndrome. Conversely, induced metabolic dysregulation by genetic or dietary means has a profound impact on the circadian oscillator, which highlights the extensive links between the circadian system and metabolic homeostasis, and underscores the role of circadian dysfunction as a factor in the etiology and incidence of metabolic syndrome and diabetes.
Intriguingly, rhythmic chromatin regulation plays a key role in both the generation of circadian rhythms and in their propagation. Consistent with this, my work indicates that several Jumonji C-terminal domain (JmjC) histone demethylases are key components of the circadian oscillator. In addition, several JmjC family members are involved in the control of metabolic processes. Thus, current projects in my lab focus on understanding the role these fascinating transcription and chromatin regulators play in the circadian clock and in the bridging of the oscillator to metabolic regulation in adult tissues.
DiTacchio L, Bowles J, Shin S, Lim DS, Koopman P, Janknecht R. (2012) Transcription factors ER71/ETV2 and SOX9 participate in a positive feedback loop in fetal and adult mouse testis. J Biol Chem. 287(28):23657-66.
Vollmers C,*, Hatori M*, Zarrinpar A, DiTacchio L*, Bushong E, Gill S, LaBlanc M, Fitzpatrick J, Ellisman M, and Panda S. (2012) Time-restricted feeding prevents adverse effects of a high-fat diet. Cell Metabolism, 15(6):848-60. * co-first authorship
Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, Chong LW, DiTacchio L, Atkins AR, Glass CK, Liddle C, Auwerx J, Downes M, Panda S, Evans RM. (2012) Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature, 485(7396):123-7.
DiTacchio L, Le HD, Vollmers C, Witcher M, Seacombe J and Panda S. (2011) Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333, 1881-5.
Jones MA, Covington MF, DiTacchio L, Vollmers C, Panda S, Harmer SL. (2010) Jumonji domain protein JMJD5 functions in both the plant and human circadian systems. Proc Natl Acad Sci U S A. 107(50):21623-8.
Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S. (2009) Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc. Natl. Acad. Sci. USA 106, 21453-8.
Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM. (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437-40.
Hitomi K, DiTacchio L, Arvai AS, Yamamoto J, Kim ST, Todo T, Tainer JA, Iwai S, Panda S, Getzoff ED. (2009) Functional motifs in the (6-4) photolyase crystal structure make a comparative framework for DNA repair photolyases and clock cryptochromes. Proc. Natl. Acad. Sci. USA 106, 6962-7.
Hughes ME*, DiTacchio L*, Hayes KR, Vollmers C, Pulivarthy S, Baggs JE, Panda S, Hogenesch JB. (2009) Harmonics of circadian gene transcription in mammals. PLoS Genet. 5, e1000442. * co-first authorship
Baggs JE, Price TS, DiTacchio L, Panda S, Fitzgerald GA, Hogenesch JB. (2009) Network features of the mammalian circadian clock. PLoS Biol. 7, e52.
Vollmers C, Panda S, DiTacchio L*. (2008) A high-throughput assay for siRNA-based circadian screens in human U2OS cells. PLoS One 3, e3457. *corresponding author and co-first authorship
Pulivarthy SR, Tanaka N, Welsh DK, DiTacchio L, Verma IM, Panda S. (2007) Reciprocity between phase shifts and amplitude changes in the mammalian circadian clock. Proc. Natl. Acad. Sci. USA 104, 20356-61.
DiTacchio L, Panda S. (2006) Systems biology of circadian rhythms: an outlook. J. Biol. Rhythms 21, 507-18.
Knebel J*, DiTacchio L*, Janknecht R. (2006) Repression of transcription by TSGA/Jmjd1a, a novel interaction partner of the ETS protein ER71. J Cell Biochem. 99, 319-29.* co-first authorship.
DiTacchio L, Janknecht R. (2005) Cloning of the murine ER71 gene (Etsrp71) and initial characterization of its promoter. Genomics. 85, 493-502.
DiTacchio L, Janknecht R. (2002) Functional analysis of the transcription factor ER71 and its activation of the matrix metalloproteinase-1 promoter. Nucleic Acids Res. 30, 2972-9.