Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2008)

Studies in organisms from worms to humans have brought an increasing appreciation for a crucial role of the central nervous system in the regulation of many basic physiological processes including energy homeostasis, immune responses, development and aging. However, the mechanisms underlying such regulation are still incompletely understood. In C. elegans, two physiological processes that are notably modulated by the nervous system are the developmental decision to arrest in the hibernation-like dauer larval stage and the regulation of aging. In this thesis, we studied the interplay between endocrine systems controlling aging and dauer formation, such as insulin/IGF-1 signaling, and neuronal signaling, such as neurotransmitter and sensory signaling. We found that dopamine signaling may be specifically modulated by insulin/IGF-1 signaling to regulate the quiescence behavior of dauer, and it may also be involved in the process of exit from the dauer stage. Because there are physiological and molecular similarities between the dauer stage and seasonal hibernation in mammals, it is possible that dopamine signaling contributes to behavioral quiescence in hibernating mammals. In a separate study, we found that signals from the sensory system feed into the regulation of at least two different transcription factors, the FOXO homolog daf-16 and the steroid nuclear hormone receptor daf-12, both targets of endocrine pathways. In addition, we found that the sensory system is required for normal expression of immune response genes, and that sensory system mutants have increased susceptibility to a bacterial pathogen. These results indicate that sensory inputs can coordinately regulate several processes by affecting a number of important transcriptional responses. The insulin/IGF-1 pathway, the dopamine pathway and sensory inputs are crucial in the mammalian central nervous system for the regulation of many physiological as well as behavioral responses. Therefore these studies in a simpler, genetically tractable organism may offer valuable insights on how these systems may be coordinated in higher organisms.

    Cover page: Dopamine modulation of quiescence in dauer larvae, and other investigations on hibernation and lifespan in C. elegans
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2010)
    The ability to control cellular and viral gene expression, either globally or selectively, is central to a successful viral infection, and it is also crucial for the host to respond and eradicate pathogens. In eukaryotes, regulation of message stability contributes significantly to the control of gene expression and plays a prominent role in the normal physiology of a cell as well as in its response to environmental and pathogenic stresses. Not surprisingly, emerging evidence indicates that there are significant interactions between the eukaryotic RNA turnover machinery and a wide variety of viruses. Interestingly, in many cases viruses have evolved mechanisms not only to evade eradication by these pathways, but also to manipulate them for enhanced viral replication and gene expression. Given our incomplete understanding of how many of these pathways are normally regulated, viruses should be powerful tools to help deconstruct the complex networks and events governing eukaryotic RNA stability.
      Cover page: Viruses and the cellular RNA decay machinery
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2015)
      Many viruses express factors that reduce host gene expression through widespread degradation of cellular mRNA. An example of this class of proteins is the mRNA-targeting endoribonuclease SOX from the gamma-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies indicated that cleavage of messenger RNAs (mRNA) by SOX occurs at specific locations defined by the sequence of the target RNA, which is at odds with the down-regulation of a large portion of cellular transcripts. In this study, we address this paradox by using high-throughput sequencing of cleavage intermediates combined with a custom bioinformatics-based analysis pipeline to identify SOX cleavage sites across the mRNA transcriptome. These data, coupled with targeted mutagenesis, reveal that while cleavage sites are specific and reproducible, they are defined by a degenerate sequence motif containing a small number of conserved residues rather than a strong consensus sequence. This degenerate element is well represented in both human and KSHV mRNA, and its presence correlates with RNA destabilization by SOX. This represents a new endonuclease targeting strategy, in which use of a degenerate targeting element enables RNA cleavage at specific locations without restricting the range of targets. Furthermore, it shows that strong target selectivity can be achieved without a high degree of sequence specificity.
        Cover page: Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX
        Top