Ying-Hui Fu

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Ying-Hui Fu (傅嫈惠)
Residence San Francisco, CA
Spouse(s) Louis Ptáček
Scientific career
Fields Neuroscience, Genetics, Neuroscience of sleep
Institutions UCSF
Website http://www.neugenes.org/outreach.htm

Ying-Hui Fu (Chinese: 傅嫈惠) is a biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.[1]

Background and education[edit]

Early career[edit]

In 1980, Fu received a degree in food science from National Chung-Hsing University in Taiwan. In her study of food sciences, she was introduced to biochemistry and microbiology, which led her to study DNA manipulation. She then received her Ph.D. in biochemistry and molecular biology from Ohio State University in 1986. She continued to work at OSU for three more years in a post-doctoral position studying gene regulation in fungi. During her time at OSU, she cloned numerous genes important for nitrogen and sulfur metabolism in Neurospora. One of these genes, cys-3, encodes a leucine zipper protein. It was hypothesized that leucine zippers were DNA-binding elements. The first proof of this in living organisms was a mutation in the cys-3 leucine zipper, which caused a sulfur metabolism defect. After studying the mutation, Fu demonstrated that the mutated cys-3 was unable to bind DNA.[2]

In 1989, Fu transferred to the Baylor College of Medicine as a post-doctoral fellow to study human genetics.[3] While there, she was part of the team that identified the fragile-X syndrome gene. The gene contains a polymorphic CGG trinucleotide repeat in their DNA sequence; the repeat ranged from 6 to 54 in individuals with normal X chromosomes. The transition from stable to unstable occurred between 46 to 52 repeats. The instability increases the likelihood of fragile-X mental retardation.[4] The repeats have a tendency to expand in transmission through meiosis. The size of the repeat correlates with severity of the disease.[5] Fu cloned one of the genes responsible for a form of muscular dystrophy called myotonic dystrophy, and showed that an expanded trinucleotide repeat in this gene also was unstable and caused the disease. Together, these discoveries characterized the molecular basis of genetic “anticipation,” the phenomenon of worsening severity in subsequent generations, as being due to unstable, expanded trinucleotide repeats.[6]

Biomedical industry[edit]

After her postdoc position, Fu worked in biotech industry for four years before returning to academia. She worked first for two years from January 1993 - 1995 at Millennium Pharmaceutical Corporation, a biopharmaceutical company focused on oncology and inflammation (later acquired by Takeda Pharmaceutical Company). After leaving Millennium Pharmaceutical, from 1995- August 1997 Fu worked for Darwin Molecular Corporation for two years and took part in the search for the mutations responsible for premature aging (Werner Syndrome) and early onset Alzheimer's Disease (Presinilin 2).[2]

Recent career[edit]

In 1997, Fu returned to academia, taking the position of associate professor of research at the University of Utah. Fu was then recruited to the University of California, San Francisco in 2002, where she is a co-principal investigator (PI) with her collaborator, Louis Ptacek.[3] The lab's current projects include: locating human sleep genes, uncovering the molecular mechanisms of human sleep regulation and human circadian rhythms, investigating mouse models with de/dys-myelinating disease, and classifying miRNAs that contribute to healthy myelin.

Research interests[edit]

Human sleep behaviors[edit]

Circadian rhythms and metabolism[edit]

Fu had her training in molecular biology and human genetics, but she became interested in circadian rhythms in 1996 when a woman came into a sleep clinic at the University of Utah, complaining that she had to go to bed very early and would wake up very early. This woman and her family would become the subject of study for Fu and her collaborator Louis Ptacek for familial advanced sleep phase syndrome (FASPS). They cloned the causative gene/mutation and studied the in vitro biochemical consequences of the mutation, culminating in a 2001 paper An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome, reporting the first circadian gene mutation in humans.[7]

Familial advanced sleep phase syndrome[edit]

In 2001, Fu and her collaborator's labs published a paper that explained a phenotype of extremely early risers in humans called Familial Advanced Sleep Phase Syndrome (FASPS).[8] Humans with this autosomal dominant disease typically go to bed around 7:00 p.m. and wake up at 3:00 a.m. The lab studied the genomes of people with this trait and found a point mutation in the PER2 gene that likely causes the behavioral phenotype.

Short sleep phenotype[edit]

In 2009, Fu’s group published a paper that explained the mechanisms of a short sleep phenotype in humans.[9] In one family, carriers of the autosomal dominant phenotype sleep 6.25 hours compared to non-carrying family members, who sleep more than 8 hours per night. Fu traced the phenotype back to a point mutation in a gene called DEC2 that is associated with short sleep phenotype in humans. The mutant DEC2 has a proline-to-arginine switch at amino acid position 384, which causes the short sleep phenotype. Transgenic mice and flies with the mutant DEC2 showed similar phenotypes. It is not currently known what other molecules DEC2 interacts with to produce the short sleep phenotype.

Neurodegeneration[edit]

Trinucleotide repeat expansions and neurological diseases[edit]

When Fu did her post-doctoral work in Baylor College, she was part of the team that was positional cloning the Fragile-X syndrome gene. There, she studied the trinucleotide repeat sequence expansions, the mutations responsible for the Fragile-X Syndrome, and their correlation with disease severity and age of onset. This work led to the discovery of underlying molecular mechanism for genetic anticipation. Following this work, she cloned the gene responsible for Myotonic dystrophy based on the hypothesis that genetic anticipation in Myotonic dystrophy is also caused by trinucleotide repeat expansion on patient DNA. This mutational mechanism is now known to cause not only Fragile X syndeome and Myotonic dystrophy, but also Huntington’s disease and many of the spinocerebellar ataxias. Thus, it is a common mutational mechanism in inherited neurological diseases.[10]

Autosomal Dominant Leukodystrophy (ADLD)[edit]

In 2006, Fu’s lab published a paper characterizing a mutation that led to ADLD in humans. Adult-onset autosomal dominant leukodystrophy (ADLD) is a neurological disorder that is associated with widespread myelin loss in the central nervous system. Fu’s lab traced the phenotype back to individuals with an extra copy of nuclear laminar protein lamin B1 making ADLD one of the diseases named “laminopathies”.[11]

Recent work[edit]

The following are selected summaries of Fu's recent publications.

Human genetics and sleep behavior[edit]

Several characteristic genetic mutations from subjects with advanced sleep phase (FASPS) were identified. Mutations on T44A and H46R in CK1δ gene inserted into mouse model showed shortened circadian rhythm; Drosophila carrying the same transgene, however, have lengthened circadian rhythm. This result suggests clock regulatory differ between the two species.[12] Phenotypes akin to CK1δ gene mutation also occurs in mutations such as S662G in per2 gene.[13] Mutations in P415A/H417R of per3 gene have been showed to cause changes in molecular circadian rhythm and are potentially linked to seasonal mood trait.[14] and A260T in cry2 gene.[15] Fu's lab also identified a mutation (P384R) on DEC2 gene that leads to familial natural short sleep (FNSS) phenotype. Mutations at these gene loci affect biological clock result in shortened intrinsic periods.[16]

Post-translational modification in circadian rhythm[edit]

This review paper highlighted the essential role of post-translational phosphorylation in maintaining circadian rhythm. Post-translational phosphorylation not only stabilizes the PER1/PER3 complex, but also controls the PER protein entry to the nucleus, thus allowing PER protein to fulfill its role of inhibiting the activator of PER transcription.[17][18]

Cry2 mutation and advanced sleep phase in human[edit]

The cry2 mutation identified in position 260 (A260T) affects the cofactor (FAD) binding domain of CRY2. This mutation alters CRY2 conformation, increasing binding affinity of FBXL3, which ultimately promotes CRY2 degradation.[15]

Per3 variant relates to seasonal mood trait and causes a circadian phenotype[edit]

This paper highlighted the connection between sleep and mood in humans. Fu's lab identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in individuals with familial advanced sleep phase syndrome accompanied by higher depression.[14]

Awards[edit]

Sleep Science Award from the American Academy of Neurology (2006)

Bauer Foundation Colloquium Distinguished Guest, Brandeis University, Boston, MA (2006)

Distinguished Guest, Bollum Symposium, University of Minnesota, Minneapolis, MN (2008)

Distinguished visiting professorship, Tamkang University, Taiwan (2009)

Faculty Research Lecture in Basic Research, UCSF (2012)

Presidential Lecture, University of Vermont (2012)

Elected Member, National Academy of Sciences (2018)

Selected publications[edit]

  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 B1duplications cause autosomal dominant leukodystrophy. Nat Genet. 2006 Oct ; 38(10)1114-23. Epub 2006 Sep 3.
  4. 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.
  5. Fu, YH and Marzluf, GA. cys-3, the positive-acting sulfur regulatory gene of Neurospora crassa, encodes a sequence-specific DNA-binding protein. J Biol Chem, 1990, 265, 11942-11947.
  6. Fu, Y.H., Kuhl, D.P., Pizzuti, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell, 1991, 67, 1047-1058.
  7. Fu, Y.H., Pizzuti, A., Fenwick, R.G., Jr., et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science, 1992, 255, 1256-1258.
  8. Yu, C.E., Oshima, J., Fu, Y.H., et al. Positional cloning of the Werner's syndrome gene. Science, 1996, 272, 258-262.
  9. Levy‑Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wejsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, 1995 269, 973-977.
  10. 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.
  11. Kaasik K, Kivimäe S, Allen JJ, Chalkley RJ, Huang Y, Baer K, Kissel H, Burlingame AL, Shokat KM, Ptáček LJ, Fu Y-H*. Glucose Sensor O-GlcNAcylation Coordinates with Phosphorylation to Regulate Circadian Clock.Cell Metab. 2013 Feb 5;17(2):291-302.
  12. Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, Lee HY, Jones CR, Fu YH, Charles AC, Ptacek LJ. Casein kinase iδ Mutations in Familial Migraine and Advanced Sleep Phase.Science Transitional Mag. 2013 May 1; 183(5):183ra56.
  13. 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.
  14. Kaasik K, Kivimäe S, Allen JJ, Chalkley RJ, Huang Y, Baer K, Kissel H, Burlingame AL, Shokat KM, Ptácek LJ, Fu YH. Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 2013 Feb 5; 17(2):291-302. PMID 23395175; PMC 3597447.

See also[edit]

References[edit]

  1. ^ Bai, Nina (2018-05-02). "2 UCSF Faculty Elected to the National Academy of Sciences for 2018". UC San Francisco. Retrieved 2018-10-14.
  2. ^ a b "Science of Sleep - Biography". Science of Sleep.
  3. ^ a b "Neurogenetics: Ying-Hui Fu". www.neugenes.org. Retrieved 2015-04-09.
  4. ^ Schepens, Bert; Tinton, Sandrine A.; Bruynooghe, Yanik; Beyaert, Rudi; Cornelis, Sigrid (2005-01-01). "The polypyrimidine tract-binding protein stimulates HIF-1α IRES-mediated translation during hypoxia". Nucleic Acids Research. 33 (21): 6884–6894. doi:10.1093/nar/gki1000. ISSN 0305-1048. PMC 1310900. PMID 16396835.
  5. ^ HOLLMAN, A (2017-04-27). "Dr Carey Coombs and his non-existent cardiac infarct". Heart. 83 (5): 582. doi:10.1136/heart.83.5.582h. ISSN 1355-6037. PMC 1760838. PMID 10836841.
  6. ^ Plassart, E.; Fontaine, B. (1994). "Genes with triplet repeats: a new class of mutations causing neurological diseases". Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. 48 (5–6): 191–197. doi:10.1016/0753-3322(94)90133-3. ISSN 0753-3322. PMID 7999979.
  7. ^ Reddy, Sumathi (June 9, 2014). "Scientists Search for the Best Sleepers". Wall Street Journal. ISSN 0099-9660. Retrieved April 21, 2015.
  8. ^ Toh, KL (2001). "An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome". Science. 291: 1040–3. doi:10.1126/science.1057499. PMID 11232563.
  9. ^ He, Y (2009). "Transcriptional suppressor DEC2 is a Regulator for Human Sleep Homeostasis". Science. 325: 866. doi:10.1126/science.1174443. PMC 2884988. PMID 19679812.
  10. ^ Macdonald, M (Mar 26, 1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell. 72 (6): 971–983. doi:10.1016/0092-8674(93)90585-e. ISSN 0092-8674. PMID 8458085.
  11. ^ Padiath, Quasar Saleem; Fu, Ying-Hui (2010). "Autosomal dominant leukodystrophy caused by lamin B1 duplications a clinical and molecular case study of altered nuclear function and disease". Methods in Cell Biology. 98: 337–357. doi:10.1016/S0091-679X(10)98014-X. ISSN 0091-679X. PMID 20816241.
  12. ^ Takahashi, Joseph S.; Hong, Hee-Kyung; Ko, Caroline H.; McDearmon, Erin L. (2008). "The genetics of mammalian circadian order and disorder: implications for physiology and disease". Nature Reviews Genetics. 9 (10): 764–775. doi:10.1038/nrg2430. PMC 3758473. PMID 18802415.
  13. ^ Ko, Caroline H.; Takahashi, Joseph S. (2006-10-15). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 (suppl_2): R271–R277. doi:10.1093/hmg/ddl207. ISSN 0964-6906. PMC 3762864. PMID 16987893.
  14. ^ a b Martynhak, Bruno Jacson; Hogben, Alexandra L.; Zanos, Panos; Georgiou, Polymnia; Andreatini, Roberto; Kitchen, Ian; Archer, Simon N.; Schantz, Malcolm von; Bailey, Alexis (2017-01-10). "Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3−/− mice, but not wildtype mice". Scientific Reports. 7: 40399. doi:10.1038/srep40399. ISSN 2045-2322. PMC 5223197. PMID 28071711.
  15. ^ a b Patke, Alina; Murphy, Patricia J.; Onat, Onur Emre; Krieger, Ana C.; Özçelik, Tayfun; Campbell, Scott S.; Young, Michael W. (2017-04-06). "Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder". Cell. 169 (2): 203–215.e13. doi:10.1016/j.cell.2017.03.027. ISSN 0092-8674. PMC 5479574. PMID 28388406.
  16. ^ Brown, Ritchie E.; Basheer, Radhika; McKenna, James T.; Strecker, Robert E.; McCarley, Robert W. (2012-07-01). "Control of Sleep and Wakefulness". Physiological Reviews. 92 (3): 1087–1187. doi:10.1152/physrev.00032.2011. ISSN 0031-9333. PMC 3621793. PMID 22811426.
  17. ^ Atger, Florian; Mauvoisin, Daniel; Weger, Benjamin; Gobet, Cédric; Gachon, Frédéric (2017-01-01). "Regulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms". Frontiers in Endocrinology. 8. doi:10.3389/fendo.2017.00042. ISSN 1664-2392. PMC 5340782. PMID 28337174.
  18. ^ Ballesta, Annabelle; Innominato, Pasquale F.; Dallmann, Robert; Rand, David A.; Lévi, Francis A. (2017-03-28). "Systems Chronotherapeutics". Pharmacological Reviews. 69 (2): 161–199. doi:10.1124/pr.116.013441.

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