Multiple 'Siblings' from Every Gene: Alternate Gene Reading Leads to Alternate Gene Products
ScienceDaily (July 13, 2011) — A genome-wide survey by researchers at The Wistar Institute shows how our cells create alternate versions of mRNA transcripts by altering how they "read" DNA. Many genes are associated with multiple gene promoters, the researchers say, which is the predominant way multiple variants of a given gene, for example, can be made with the same genetic instructions.
Their findings, which appear in the journal Genome Research, available online now, show how genes are read in developing and adult brains, and identify the changes in reading DNA that accompany brain development. Changes in how the cell reads the DNA create multiple RNA variants, which can lead to alternative forms of proteins (called isoforms). The Wistar researchers discovered numerous novel gene products, many of which are alternatively used during brain development. They found that genes linked to neurological disorders produce many variants/isoforms in the brain and that the isoforms produced in medullablastoma, a highly malignant form of brain cancer, were different for some genes from the isoforms found in normal adult brains.
"If a given gene is associated with multiple promoters, it creates multiple ways for a gene to be read in different cell-types or developmental stages. Consequently, each gene can produce a bunch of alternative products, like siblings of a family, who might probably do different things at different times (developmental stages) or different places (cells)," said Ramana Davuluri, Ph.D., associate professor in the Molecular and Cellular Oncogenesis Program at Wistar, and co-director of Wistar's Center for Systems and Computational Biology. "Think of two brothers -- for example, one a high-speed jet airline pilot and the other a much slower-paced bus driver. They both shuttle people around in vehicles, but imagine the damage they could do if they switch jobs for the day."
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Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development
Sharmistha Pal1,2,4, Ravi Gupta1,2,4, Hyunsoo Kim1, Priyankara Wickramasinghe1, Valérie Baubet2, Louise C. Showe1,2,3, Nadia Dahmane2 and Ramana V. Davuluri1,2,5
-Author Affiliations
1Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19019, USA;
2Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19019, USA;
3Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania 19019, USA
4 These authors contributed equally to this work.
Abstract
Despite our growing knowledge that many mammalian genes generate multiple transcript variants that may encode functionally distinct protein isoforms, the transcriptomes of various tissues and their developmental stages are poorly defined. Identifying the transcriptome and its regulation in a cell/tissue is the key to deciphering the cell/tissue-specific functions of a gene. We built a genome-wide inventory of noncoding and protein-coding transcripts (transcriptomes), their promoters (promoteromes) and histone modification states (epigenomes) for developing, and adult cerebella using integrative massive-parallel sequencing and bioinformatics approach. The data consists of 61,525 (12,796 novel) distinct mRNAs transcribed by 29,589 (4792 novel) promoters corresponding to 15,669 protein-coding and 7624 noncoding genes. Importantly, our results show that the transcript variants from a gene are predominantly generated using alternative transcriptional rather than splicing mechanisms, highlighting alternative promoters and transcriptional terminations as major sources of transcriptome diversity. Moreover, H3K4me3, and not H3K27me3, defined the use of alternative promoters, and we identified a combinatorial role of H3K4me3 and H3K27me3 in regulating the expression of transcripts, including transcript variants of a gene during development. We observed a strong bias of both H3K4me3 and H3K27me3 for CpG-rich promoters and an exponential relationship between their enrichment and corresponding transcript expression. Furthermore, the majority of genes associated with neurological diseases expressed multiple transcripts through alternative promoters, and we demonstrated aberrant use of alternative promoters in medulloblastoma, cancer arising in the cerebellum. The transcriptomes of developing and adult cerebella presented in this study emphasize the importance of analyzing gene regulation and function at the isoform level.
Footnotes
5 Corresponding author.
E-mail rdavuluri@wistar.org.
[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.120535.111.
Received January 7, 2011.
Accepted May 23, 2011.
Copyright © 2011 by Cold Spring Harbor Laboratory Press
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