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January 2011

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Novel small RNA molecules regulate stem cell self-renewal

By L. H. Lazarus
January 2011

Yale University School of Medicine researcher Haifan Lin, Ph.D.

In addition to his many honors, Lin was also a recipient of the 2010 NIH Director's Pioneer Award for conducting innovative and groundbreaking research. (Photo courtesy of Steve McCaw)

Mike Resnick, Ph.D.

The presentation inspired a question from NIEHS Principal Investigator Mike Resnick, Ph.D., head of the Chromosome Stability Group. (Photo courtesy of Steve McCaw)

Haifan Lin, Ph.D. speaks while Guang Hu, Ph.D. looks on

Hu, right, shown moderating the question and answer session, found Lin's research applicable to his interests. Hu added, "We study self-renewal in embryonic stem cells, and we could apply similar approaches Dr. Lin pioneered in his work." (Photo courtesy of Steve McCaw)

Christina Teng, Ph.D.

Christina Teng, Ph.D., above, is a molecular biologist in the NTP Biomolecular Screening Branch. (Photo courtesy of Steve McCaw)

Yale University School of Medicine researcher Haifan Lin, Ph.D., visited NIEHS recently to talk about exciting new discoveries he has made with stem cells. His presentation discussed the epigenetic regulation of stem cells by novel small RNA molecules and included information on the involvement of stem cells in diseases such as testicular and intestinal cancer. Laboratory of Molecular Carcinogenesis Principal Investigator Guang Hu, Ph.D., hosted the Dec. 14 seminar as part of the NIEHS Distinguished Lecture Series.

Lin( Exit NIEHS, director of the Yale Stem Cell Center and professor of Cell Biology and Genetics, began with an overview of his discovery of the Argonaute (AGO)/PIWI family of proteins. He stated, "This family contains highly conserved sequences that exist throughout evolution in both animal and plant kingdoms. The ago/piwi family of genes represents the only known genes required for stem cell regulation." 

According to Hu, the impact of Lin's work "greatly enhanced our understanding about adult stem cell maintenance and self-renewal, and will contribute to the development of stem cell therapies and regenerative medicine using adult stem cells." Lin's presentation, he continued, "was very inspirational to me and people in my group."

Using fly and mouse cells to study cancer

Lin uses Drosophila and mouse model systems to explore the asymmetric division of stem cell self-renewal. His research determined that over-proliferation of stem cells leads to cancer, while under-proliferation leads to tissue dystrophy, anemia, immunodeficiency, or infertility.

An important attribute of the AGO/PIWI proteins is their ability to bind to a class of non-coding small RNA molecules, termed PIWI-interacting RNAs (piRNAs). piRNAs consist of a class of small regulatory RNAs, which are slightly larger than other known classes of regulatory RNAs.

Lin summarized four salient features of piRNAs:

  • More than 60,000 species exist.
  • They lack sequence consensus, except for partial homogeneity at the 5' terminus.
  • They are derived from selective loci on chromosome 17 in mice and may be transcribed from a single precursor RNA.
  • They are associated with intergenetic repetitive sequences in genes and transposons, DNA sequences that move to new positions within the genome. 

Evidence for the PIWI-piRNA complex

The determinant factor for epigenetic regulation by piRNAs relies on its binding to the amino acid sequence in PIWI, Lin explained. Site-specific mutation analysis of PIWI and its molecular docking with piRNA verified its role in the development of stem cells in testis germinal epithelium.

Lin stressed that PIWI-piRNA complexes and related proteins play central roles in biological systems ranging from the fruit fly Drosophila to humans. He continued, "The PIWI-piRNA complex is the key component that interacts with canonical components in genetics."

Early studies demonstrated that overexpression of PIWI increased the number of egg chambers in Drosophila ovaries. A comparable study using testicular tissue with HIWI, the human analog, revealed a correlation between overexpression of HIWI and cancer of the germinal epithelium of the testis, also known as seminomas.

Lin also talked about HIWI's involvement in intestinal cancer. While HIWI is found in stem cells in normal gastric mucosa, its over-expression leads to ectopic gastric cancers, such as atrophic gastritis and intestinal metaplasia. Lin reiterated, "Reducing HIWI inhibits the formation of cancer."

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