Ying-Hui Fu

Ying-Hui Fu (傅嫈惠) is a biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her lab’s chief discoveries have been to describe Mendelian sleep phenotypes and to identify causative genes and mutations for circadian rhythm sleep schedule and sleep duration behavioral traits in humans. In separate work, her group has characterized interesting genetic forms of demyelinating degenerative disorders. Her work focuses on studying interesting heritable traits in humans, linking them back to changes in DNA, and using animal models, in combination with molecular cellular and biochemical methods, to further explore the mechanisms underlying various phenotypes. Fu is currently a professor of neurology at the University of California, San Francisco where her lab is focusing on studies of human sleep behavioral traits.

Background and education

Early career

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 and its uses in the study of biological function. She then received her Ph.D. in biochemistry and molecular biology from Ohio State University in 1986. She continued to work at Ohio State 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, 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, she showed that the cys-3 bound to DNA and that the mutation abrogated the DNA-binding.^[1]

She next went to the Baylor College of Medicine as a post-doctoral fellow to study human genetics in 1989.^[2] While there, she was part of the team that identified the Fragile-X syndrome gene. The gene contains a polymorphic trinucleotide DNA repeat. She showed that once the repeats expanded outside of the normal range, that they caused Fragile X mental retardation and became unstable. The repeats have a tendency to expand in transmission through meiosis. The size of the repeat correlated with severity of the disease. She also cloned the gene responsible for Myotonic dystrophy and showed that an expanded trinucleotide repeat in this gene also was unstable and caused Myotonic dystrophy. 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.^[3]

Biomedical industry

After her postdoc position, Fu worked in biotech industry for four years before returning to academia. She worked for two years for Millennium Pharmaceutical Corporation, a biopharmaceutical company focused on oncology and inflammation (later acquired by Takeda Pharmaceutical Company); after leaving Millennium Pharmaceutical, she worked for Darwin Molecular Corporation for two years and was part of the team finding the mutations responsible for premature aging (Werner Syndrome) and early onset Alzheimer (Presinilin 2).^[1]

Recent career

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.^[2]

Sleep and circadian rhythm research

Circadian rhythms

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 (FASP). They cloned the causative gene/mutation and studied the in vitro biochemical consequences of the mutation, culminating in a 2001 research paper reporting the first circadian gene mutation in humans.^[4]

Familial advanced sleep phase syndrome

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 (FASP). 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.

According to Google Scholar, this PER2 paper has been cited 959 times as of April 2015, making it one of the most influential papers in circadian biology. It was the first human circadian disorder to be well characterized at the genome levels.^[5]

In people from this family with FASP, a serine is changed to a glycine at amino acid site 662 in the human PER2 protein. PER2 is part of the core circadian clock in mammals. Subsequent work concluded that the point mutation alters a site in the PER2 protein that is normally regulated by phosphorylation and O-GlcNAcylation.^[6] Transgenic mice carrying the mutant human PER2 gene mimic FASP humans very closely.

In further characterization of FASP, Fu's lab found an additional mutation in a novel circadian gene in another FASPS family. Fu’s lab found that a missense mutation in the CK1δ gene, which is responsible for phosphorylating PER2 and other proteins, could also lead to an FASP phenotype. CK1δ from the mutant gene had decreased enzymatic activity in vitro.^[7]

Short sleep phenotype

In 2009, Fu’s group published a research paper that explained the mechanisms of a short sleep phenotype in humans. 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.

DEC2 belongs to the basic helix-loop-helix (BHLH) protein superfamily and in general acts as transcriptional repressor. DEC2 has an E-box, which makes it an output of the core circadian clock. DEC2 can bind to E-boxes to repress its own transcription. DEC2 has also been shown to be involved in the regulation of growth factors and hormones.

Discoveries outside circadian rhythms and sleep

Trinucleotide repeat expansions and neurological diseases

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.^[8]

Autosomal Dominant Leukodystrophy (ADLD)

In 2007, 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”.^[9]

Awards

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

Selected publications

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.

See also

• Neuroscience of sleep

References

External links

• Official profile at University of California