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Neuroscience Graduate Program at UCSF

Faculty - Ying-Hui Fu, Ph.D.

Molecular Study of Human Sleep Behaviors


Research Description

Our research focuses on hereditary neuro-related conditions, in particular circadian rhythm/sleep duration behavior traits. We collaborate closely with Dr. Louis Ptáček’s Laboratory. All of the work in our laboratory begins with human families segregating alleles for monogenic traits. Study of DNA from these families allows identification of the gene/mutation(s) responsible for the phenotype. In vitro studies of the wild-type and mutant proteins encoded by the gene then provide a window into relevant biological pathways and pathophysiology. In addition, we use model organisms such as mouse and fruit fly to probe physiology in vivo. The pursuit of the genetic and molecular basis of human behavior is extremely complex because of the wide variation in "normal" individuals. Furthermore, behaviors such as sleep are confounded by social and familio-cultural influences that frequently lead us to override our biological clock and stay up later or to wake up earlier than we otherwise would or shorten sleep duration. Various agents including caffeine and alcohol also confound one's ability to understand the inherent rhythms and sleep homeostasis dictating humans' activities. We have identified many and are still in the process of identifying more mutations that are involved in regulation of human rhythmicity and sleep duration. Our long-term goal is that as we find more mutations that are affecting human sleep behavioral patterns, we will characterize these mutations to assist us understand human circadian clock and sleep duration regulation.

Circadian and sleep schedule biology
Most organisms live in a continuously changing environment that varies in a rhythmic fashion related to the Earth’s rotation around its axis. This planetary movement produces a daily solar cycle with a periodicity of approximately 24-hr. Organisms have evolved an internal clock that responds to the daily solar cycle resulting in cycling of many physiological and behavioral responses with a period of about 24-hr. Disruption of circadian rhythmicity has been linked to many human disorders including insomnia, jet lag, stomach ailments, cardiovascular disease, depression, and cancer. We have collected many probands/families with autosomal dominant advanced sleep phase (FASP, extreme morning larks), and delayed sleep phase (FDSP, extreme night owls) traits and have identified several causative genes/mutations. Results from our studies on these mutations have yielded unexpected insights into mammalian circadian rhythm regulation.

Sleep duration variants in humans
Considering we spend one third of our lives in the state of sleep, our understanding of sleep regulation is very limited. Sleeping and waking are complex behaviors generated by elaborate mechanisms involving many areas of brain. Sleep and wakefulness and performance rhythms are diurnal rhythms that we consciously experience on a daily basis. Sleep disruption and duration has also been shown to have significant impact on human health, quality of life, and life expectancy. We have identified mutations that cause people to have shorter sleep duration than majority of population and yet they remain active and energetic during the day. Studies of these mutations will ultimately lead us to a better understanding of the regulatory mechanism for sleep duration.

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Current Projects

Identify human sleep genes

Molecular studies of human sleep regulation

Molecular studies of human circadian rhythm regulatory mechanism

Characterize mouse models of de/dys-myelinating disease

Characterize miRNAs that are important for healthy myelin

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Lab Members

Tomas McMahon, Laboratory Manager
Douglas Chin, Research Assistant
Ying Zhang, Laboratory Assistant
William Hallows, Postdoctoral Fellow
Shen-Yi Bruce Howng, Postdoctoral Fellow
Yong Huang, Postdoctoral Fellow
S-Y Christin Chong, Postdoctoral Fellow
Luoying Zhang, Postdoctoral Fellow
Pei-Ken Hsu, Postdoctoral Fellow

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Selected Publications

Link to Publications via PubMed

  1. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptáček LJ, Fu Y-H. An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome. Science. 2001;291:1040-3.
  2. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptáček LJ, Fu Y-H. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature. 2005;434:640-4.
  3. Padiath QS, Saigoh K, Schiffman R, Asahara H, Koeppen A, Hogan K, Ptáček LJ, Fu Y-H. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet. 2006 Oct ; 38(10)1114-23. Epub 2006 Sep 3.
  4. Xu Y, Toh KL, Jones CR, Shin JY, Fu Y-H, Ptáček LJ. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell. 2007 Jan 12;128(1):59-70.
  5. He Y, Jones CR, Fujiki N, Xu Y, Guo B, Holder J, Nishino S, and Fu Y-H. Transcriptional suppressor DEC2 is a Regulator for Human Sleep Homeostasis. Science. 2009 325:866.
  6. Kaasik K, Allen JJ, Kivimae S, Chalkley R, Huang Y, Kissel H, Burlingame AL, Shokat KM,  Ptáček LJ, Fu YH. Reciprocal regulation of Circadian Clock through GSK3β and O-linked N-acetylglucosaminylation. Cell Metabolism. 2013;17:291–302.
  7. Heng MY, Lin S-T, Verret L, Huang Y,  Kamiya S, Palop JJ,  Huang EJ, Ptáček LJ, Fu Y-H. Lamin B1 Mediates Cell-Autonomous Neuropathology in a Leukodystrophy Mouse Model. J Clin Invest. 2013 June 1: 123(6):2719-29.

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Ying-Hui Fu, Ph.D.



Email

ying-hui.fu@ucsf.edu

Phone

415-502-2948

Office Address

UCSF MC 2922
Fu and Ptacek Laboratories
1550 4th Street, RH-548B
San Francisco, CA 94158

Other Websites

Biomedical Sciences Program

Lab Website

Neurogenetics Lab Website

PIBS Website