TRANSCRIPTOME DYNAMICS DURING THE MAMMALIAN CELL CYCLE Public Deposited

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  • March 20, 2019
Creator
  • Dominguez, Daniel I.
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • In recent years, technologies capable of simultaneously deciphering the nucleotide sequence and expression level of most RNAs in the cell have challenged the simplistic view of one gene-one protein. It is now well-appreciated that the cell has a tremendous level of flexibility during RNA processing (i.e. alternative splicing) to produce multiple coding mRNAs from single gene unit. Another surprising find is that most of the genome is transcribed, which leads to the production of a large proportion of RNAs without coding potential (i.e. lncRNAs). Global transcriptome rearrangements have been shown to occur during and regulate key biological processes like development and differentiation. This work focuses on bettering our current understanding of the mammalian cell cycle in the context of transcriptome-wide dynamics. Progression through the mitotic cell cycle has been shown to require periodic gene function. Conventionally, these biological oscillations are thought to be primarily mediated by transcription and protein degradation. Here we report sequencing of the human transcriptome through two continuous cell cycles, revealing periodic dynamics of over 1,000 coding and non-coding RNAs. Additionally, we uncovered widespread periodic splicing events, many of which affect genes that regulate cell cycle. Mechanistically, we show that Cdc2-like kinase 1 undergoes periodic fluctuations through an auto-inhibitory circuit to control a network of periodic splicing events that are required for cell cycle. Our findings elucidate a novel mechanism for periodic gene regulation independent of transcription, suggesting that proteome expansion via splicing adds a new regulatory layer for control of gene function during cell division.
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  • In Copyright
Advisor
  • Wang, Zefeng
Degree
  • Doctor of Philosophy
Graduation year
  • 2014
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