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Apr 16, 2013

Why Junk Is Good for the Brain

  • Junk DNA or valuable code? Researchers are now saying that specific DNA once dismissed as junk actually plays an important role in brain development and might be involved in several devastating neurological diseases. The UC San Francisco scientists says their discovery in mice is likely to further fuel a recent scramble by researchers to identify roles for long-neglected bits of DNA within the genomes of both mice and humans.

    Most DNA is not in genes. This so-called junk DNA has largely been pushed aside and neglected in the wake of genomic gene discoveries, say the UCSF scientists. In their own research, the UCSF team studies molecules called long noncoding RNA (lncRNA), which are made from DNA templates in the same way as RNA from genes.

    “The function of these mysterious RNA molecules in the brain is only beginning to be discovered,” says Daniel Lim, M.D., Ph.D., assistant professor of neurological surgery, a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

    Alexander Ramos, a student enrolled in the M.D./Ph.D. program at UCSF, conducted extensive computational analysis to establish guilt by association, linking lncRNAs within cells to the activation of genes. Ramos looked specifically at patterns associated with particular developmental pathways or with the progression of certain diseases. He found an association between a set of 88 long noncoding RNAs and Huntington’s disease. He also found weaker associations between specific groups of long noncoding RNAs and Alzheimer’s disease, convulsive seizures, major depressive disorder, and various cancers.

    Unlike messenger RNA, which is transcribed from the DNA in genes and guides the production of proteins, lncRNA molecules do not carry the blueprints for proteins. Because of this, they were long thought to not influence a cell’s fate or actions. But lncRNAs also are transcribed from DNA in the same way as messenger RNA, and they also consist of unique sequences of nucleic acid building blocks, the team notes.

    Evidence indicates that lncRNAs can tether structural proteins to the DNA-containing chromosomes, and in so doing indirectly affect gene activation and cellular physiology without altering the genetic code. Thus, within the cell, lncRNA molecules act epigenetically, not through changes in DNA.

    The brain cells that the scientists focused on the most give rise to various cell types of the central nervous system. They are found in a region of the brain called the subventricular zone, which directly overlies the striatum. This is the part of the brain where neurons are destroyed in Huntington’s disease, which triggered by a single genetic defect.

    Ramos combined several advanced techniques for sequencing and analyzing DNA and RNA to identify where certain chemical changes happen to the chromosomes, and to identify lncRNAs on specific cell types found within the central nervous system. The research revealed roughly 2,000 such molecules that had not previously been described, out of about 9,000 thought to exist in mammals ranging from mice to humans.

    The study was published online April 11 in the journal Cell Stem Cell, in a paper titled “Integration of Genome-wide Approaches Identifies lncRNAs of Adult Neural Stem Cells and Their Progeny In Vivo”.


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