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Introns Influence Chromatin Structure and Gene Expression

  • Author(s): Plocik, Alex Matthew
  • Advisor(s): Guthrie, Christine
  • et al.
Abstract

Eukaryotic genes are littered with intervening sequences, or introns, that are transcribed, but must be precisely excised from a messenger RNA before it can be properly translated into protein. While introns were once regarded as "junk DNA," they are not inconsequential. However, we currently lack the knowledge to accurately predict the functions, if any, of individual introns in any organism. Here, I describe efforts to better understand the evolution and function of introns, with the vision that we will soon be able to identify important introns and predict their functions.

In Chapter 2, my colleagues and I describe an unexpected consequence of intron presence on chromatin structure, which suggests that introns have a broader influence on the biology of eukaryotes than previously appreciated. By analyzing published surveys of nucleosomes and 41 chromatin marks in humans, we show that 5' intronic and 3' exonic regions of active genes are differentially marked by characteristic chromatin marks, thus contributing substantially to the patterns of histone modifications within active genes. Intriguingly, these modification patterns were stable despite dramatic changes in the frequency of splice site usage at two alternative spliced genes. Thus, similar to promoter marks, which are relatively stable to differences in productive transcription, we propose that intronic and exonic chromatin marks reflect exon definition, rather than splicing per se.

In Chapter 3, I describe my work to better understand why certain introns persist in eukaryotic genomes. Using comparative genomics, I show that the ribosomal protein genes of Saccharomyces cerevisiae have greatly resisted intron loss. Mimicking the effect of intron loss with directed mutagenesis, I perform experimental tests that demonstrate that these introns do not promote gene expression, but rather, provide a means for regulation. Specifically, I show that the genes encoding ribosomal protein S9, both in S. cerevisiae and Drosophilia melanogaster, autoregulate in an intron-dependent manner. Lastly, I summarize published gene expression data from diverse animals, which suggest that multiple forms of alternative splicing have evolved to autoregulate S9 gene expression. Thus, I propose that the introns of eukaryotic genes persist, in part, due to their propensity to evolve regulatory function.

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