Our long term goal is to describe in the language of genetics and biochemistry the feedback cycles and pathways that comprise intracellular circadian systems - how they work, how they are synchronized with the environment, and how time information generated by them is used to regulate the behavior of cells. This proposal focuses on the model system Neurospora, as well as on the mouse and mammalian cell lines, to understand the paradigms underlying circadian control of cell physiology and metabolism. We also continue a longstanding effort aimed at understanding circadian photoreception and photobiology in Neurospora and use this to break new ground on a salient fungal pathogen. Our work has three foci. One Focus anticipates a global analysis and description of the circadian output network in Neurospora, using RNA sequencing, chromatin immunoprecipitation, and bioinformatics to describe the regulatory hierarchy governing circadian regulation of transcription in a cell. Then, using the exceptional background of biochemical genetics available in Neurospora, we will track the metabolic activities carried out by the proteins encoded by clock-controlled genes, and as foci of clock-controlled activities emerge, we will begin to lay the spectrum of clock-controlled processes on the Neurospora metabolic map to see how the clock regulates metabolism and physiology. In the second Focus, we will apply our knowledge of circadian output pathways to mammalian cells, using RNA sequencing to determine the circadian profile of clock-controlled genes in adipocytes and in macrophages from wt and RIP140 knockout mice. We will use RNA-seq to characterize the transcriptomes of WT and mutant cells and use chromatin immunoprecipitation to begin to dissect the role of this co-activator/co-repressor in the circadian biology of these important cell types. These experiments will probe the significance of circadian regulation to fat metabolism and to immune function in a mammal, with the hope of gaining insights into the incidence in humans of diabetes, metabolic syndrome, time-of-day differences in immune function. A third Focus is in photobiology. We will explore the mechanism whereby light activates the principal fungal photoreceptor, and extend analysis of photobiology in the important fungal pathogen Aspergillus fumigatus. We envision and will test a way to exploit our understanding of fungal photobiology to enable a new treatment for hundreds of thousands of patients with aspergillosis. These projects are complementary and mutually enriching in that they each rely on genetic and molecular techniques to dissect, and ultimately to understand, the response of cells to their environment and the organization of eukaryotic cells as a function of time.

Public Health Relevance

Biological clocks work in all cells of the human body to regulate metabolism. By studying cells of mammals, as well as cells of a fungus, we can understand how clock control works, how jet lag happens, and how clock malfunction leads to diseases like diabetes and mental illness.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TRN-7 (MR))
Program Officer
Sesma, Michael A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Schools of Medicine
United States
Zip Code
Chen, Shan; Fuller, Kevin K; Dunlap, Jay C et al. (2018) Circadian Clearance of a Fungal Pathogen from the Lung Is Not Based on Cell-intrinsic Macrophage Rhythms. J Biol Rhythms 33:99-105
Zhou, Xiaoying; Wang, Bin; Emerson, Jillian M et al. (2018) A HAD family phosphatase CSP-6 regulates the circadian output pathway in Neurospora crassa. PLoS Genet 14:e1007192
Fuller, Kevin K; Dunlap, Jay C; Loros, Jennifer J (2018) Light-regulated promoters for tunable, temporal, and affordable control of fungal gene expression. Appl Microbiol Biotechnol 102:3849-3863
Hughes, Michael E; Abruzzi, Katherine C; Allada, Ravi et al. (2017) Guidelines for Genome-Scale Analysis of Biological Rhythms. J Biol Rhythms 32:380-393
Dunlap, Jay C; Loros, Jennifer J (2017) Making Time: Conservation of Biological Clocks from Fungi to Animals. Microbiol Spectr 5:
Olivares-Yañez, Consuelo; Emerson, Jillian; Kettenbach, Arminja et al. (2016) Modulation of Circadian Gene Expression and Metabolic Compensation by the RCO-1 Corepressor of Neurospora crassa. Genetics 204:163-76
Kowalski, Caitlin H; Beattie, Sarah R; Fuller, Kevin K et al. (2016) Heterogeneity among Isolates Reveals that Fitness in Low Oxygen Correlates with Aspergillus fumigatus Virulence. MBio 7:
Hurley, Jennifer M; Loros, Jennifer J; Dunlap, Jay C (2016) Circadian Oscillators: Around the Transcription-Translation Feedback Loop and on to Output. Trends Biochem Sci 41:834-846
Conrad, Karen S; Hurley, Jennifer M; Widom, Joanne et al. (2016) Structure of the frequency-interacting RNA helicase: a protein interaction hub for the circadian clock. EMBO J 35:1707-19
Fuller, K K; Dunlap, J C; Loros, J J (2016) Fungal Light Sensing at the Bench and Beyond. Adv Genet 96:1-51

Showing the most recent 10 out of 15 publications