Transcripts of Unknown Function in Eukaryotic Cells: Lessons Forgotten and ReLearned
Gingeras, Thomas R., Affymetrix, Inc., Santa Clara, CA 95051
The current status of the functional annotations associated with the human
genome is in an unfinished state. The majority of current genome annotations are heavily
protein coding gene centric. This focus on protein coding genes intrinsically influences
current perceptions of how the genome is structured and regulated. This view of the
genome also has an underlying supposition that transcripts with very little coding
potential are not biologically important. However, recent experiments analyzing the sites
of transcription across large sections of the human genome have led to the conclusion that
the current human genome annotations can not account for the amounts of empirically
detected transcription. (Kapranov, et al. 2002, 2005; Rinn, et al., 2003, Kampa, et al.,
2004, Martone, et al., 2003, Cawley et al., 2004 Bertone, et al., 2004, Cheng, et. al, 2005).
Most of the detected unannotated transcription is composed of RNAs with very little
coding capacity (<100 aa). Except for the significant reduced coding capacity, these
transcripts of unknown function (TUFs) share many properties with well characterized
coding genes including: 1) processing of nuclear precursor transcripts (polyadenylation,
splicing and nuclear to cytosolic transport), 2) cell type expression specificity, 3)
correlation of their 5’ ends with promoter-like sites at which specific regulatory factors
and transcription-correlated chromatin modifications are found and 4) temporally
regulated expression correlated with cellular differentiation. TUFs have been shown to be
nuclear and cytosolic localized as both polyadenylated and non-polyadenylated
transcripts (Cheng, et al 2005). The biological functions of these TUFs have begun to be
explored using several genetic approaches. Initial results of these functional studies will
be described in both human can Drosophila cell systems. These data describe
unannotated populations of poly A+ and A-RNA transcripts which comprise a complex
architecture for the transcribed regions of the genomes and further indicate significantly
more complex strategies for transcriptional regulation than previously anticipated. It may
well be that the multifunctional importance of RNA may not have been lost during the
evolutionary ascendancy of the functional importance of proteins. This appears to be a
lesson to be relearned.
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