TUF Love for “Junk” DNA

Willingham, Aarron; Gingeras, T

doi:10.1016/j.cell.2006.06.009

Cited by 150 publications

(102 citation statements)

References 28 publications

(23 reference statements)

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“…Recent studies have suggested that the transcriptomes of eukaryotic cells are much more complex than previously thought (20)(21)(22). In yeast, for example, a large number of nonannotated intergenic and antisense RNAs have been identified, and most protein-coding genes appear to have more than one transcriptional start site, a property that leads to both long and short transcripts from the same gene (19,23).…”

Section: Possible Contribution Of Transcriptional Noise To the Pool Omentioning

confidence: 99%

Association of yeast Upf1p with direct substrates of the NMD pathway

Johansson

Spatrick

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

113

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Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades transcripts containing premature translation termination codons. Gene expression profiling experiments have shown that inactivation of the NMD pathway leads to the accumulation of both aberrant, nonsense-containing mRNAs, and many apparently wild-type transcripts. Such increases in transcript steady-state levels could arise from direct changes in the respective mRNA half-lives, or indirectly, as a consequence of the stabilization of transcripts encoding specific regulatory proteins. Here, we distinguished direct from indirect substrates by virtue of their association with the Saccharomyces cerevisiae Upf1 protein.Analyses of this dataset, and its comparison to the sets of transcripts that respectively increase or decrease in abundance when NMD is either inactivated or reactivated, indicate that the number of direct NMD substrates is larger than previously thought and that low abundance, alternatively transcribed mRNAs, i.e., mRNAs whose 5 ends are derived from previously unannotated 5 flanking sequences, comprise a significant class of direct substrates. Using thiamine metabolism as an example, we also show that apparent NMD-regulated cellular pathways may actually reflect the detection of low-abundance alternative transcripts under conditions where a pathway is repressed.microarray analysis ͉ mRNA half-lives ͉ nonsense-mediated mRNA decay ͉ translation termination ͉ Upf proteins

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Section: Possible Contribution Of Transcriptional Noise To the Pool Omentioning

confidence: 99%

Association of yeast Upf1p with direct substrates of the NMD pathway

Johansson

Spatrick

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

113

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“…(Note: We will simply call them "ncRNAs" hereafter; they are sometimes called transcripts of unknown functions [TUFs]; see Mattick and Makunin 2006;Willingham and Gingeras 2006) Among the 768 "putative ncRNAs" which were identified from our previous human large-scale full-length cDNA analyses and annotation project, FLJ (Ota et al 2004), 49 were clearly confirmed to be transcribed in HEK293 cells by RT-PCR analyses (Supplemental Fig. 3 and Supplemental Table 6).…”

Section: Characteristic Features Of "Conserved" and "Non-conserved" Pprsmentioning

confidence: 99%

“…2H). A recent stream of reports have shown that ncRNAs serve important regulatory roles (Hornstein and Shomron 2006;Willingham and Gingeras 2006) via various mechanisms, such as by sense-antisense interactions with target transcripts and by directly interacting with proteins, thereby modulating the strength of proteinprotein interactions (Mattick and Makunin 2006). A recent estimate indicated that thousands of ncRNAs are transcribed from the human genome, and at least 30% of human genes are subject to regulation by these RNAs (Lewis et al 2005).…”

Section: Genome Research 1011mentioning

confidence: 99%

Distinct class of putative “non-conserved” promoters in humans: Comparative studies of alternative promoters of human and mouse genes

et al. 2007

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Although recent studies have revealed that the majority of human genes are subject to regulation of alternative promoters, the biological relevance of this phenomenon remains unclear. We have also demonstrated that roughly half of the human RefSeq genes examined contain putative alternative promoters (PAPs). Here we report large-scale comparative studies of PAPs between human and mouse counterpart genes. Detailed sequence comparison of the 17,245 putative promoter regions (PPRs) in 5463 PAP-containing human genes revealed that PPRs in only a minor fraction of genes (807 genes) showed clear evolutionary conservation as one or more pairs. Also, we found that there were substantial qualitative differences between conserved and non-conserved PPRs, with the latter class being AT-rich PPRs of relative minor usage, enriched in repetitive elements and sometimes producing transcripts that encode small or no proteins. Systematic luciferase assays of these PPRs revealed that both classes of PPRs did have promoter activity, but that their strength ranges were significantly different. Furthermore, we demonstrate that these characteristic features of the non-conserved PPRs are shared with the PPRs of previously discovered putative non-protein coding transcripts. Taken together, our data suggest that there are two distinct classes of promoters in humans, with the latter class of promoters emerging frequently during evolution.[Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession nos. BP870448-BP873619 and BP244227-BP249739.]With the completion of the human and mouse genome sequencing projects (Waterston et al. 2002; International Human Genome Sequencing Consortium 2004) as well as the large-scale compilation of full-length cDNA information (Zhang et al. 2000;Okazaki et al. 2002;Strausberg et al. 2002;Imanishi et al. 2004;Ota et al. 2004), it has gradually become clear that the genome systems in higher mammals are far more complex than previously thought. Now, the once-dominant static view that a single locus corresponds to only one transcript and one protein has been shown to be of very limited validity. Rather, it is more common for a single locus to produce several transcript variants. In about half of human genes, on average, four different transcripts are produced by alternative splicing and as a consequence translated into proteins of divergent biological functions (Modrek and Lee 2002;Imanishi et al. 2004). Similarly, recent studies also demonstrated that diversification via transcriptional regulation is no less common in human genes (Landry et al. 2003). By use of alternative promoters (APs), which consist of different modules of transcriptional regulatory elements, diversified transcriptional regulation is enabled within a single locus (Landry et al. 2003;Carninci et al. 2005;Cheng et al. 2005;Kim et al. 2005;Kimura et al. 2006).The functional diversification of a single gene enabled by the use of alternative splices (ASs) and APs ...

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“…The microRNA pathway may contribute to post-transcriptional regulation of junD MicroRNA regulation of human genes is estimated to be prominent (X30% of human genes) (Willingham and Gingeras, 2006). The junD 681-nt 3 0 UTR harbors several microRNA target sequences predicted by the Sanger Institute database miRBase (JM Hernandez and K Boris-Lawrie, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Multiple facets of junD gene expression are atypical among AP-1 family members

et al. 2008

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JunD is a versatile AP-1 transcription factor that can activate or repress a diverse collection of target genes. Precise control of junD expression and JunD proteinprotein interactions modulate tumor angiogenesis, cellular differentiation, proliferation and apoptosis. Molecular and clinical knowledge of two decades has revealed that precise JunD activity is elaborated by interrelated layers of constitutive transcriptional control, complex post-transcriptional regulation and a collection of post-translational modifications and protein-protein interactions. The stakes are high, as inappropriate JunD activity contributes to neoplastic, metabolic and viral diseases. This article deconvolutes multiple layers of control that safeguard junD gene expression and functional activity. The activity of JunD in transcriptional activation and repression is integrated into a regulatory network by which JunD exerts a pivotal role in cellular growth control. Our discussion of the JunD regulatory network integrates important open issues and posits new therapeutic targets for the neoplastic, metabolic and viral diseases associated with JunD/AP-1 expression.

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TUF Love for “Junk” DNA

Abstract: The widespread occurrence of noncoding (nc) RNAs--unannotated eukaryotic transcripts with reduced protein coding potential--suggests that they are functionally important. Study of ncRNAs is increasing our understanding of the organization and regulation of genomes.

Cited by 150 publications

References 28 publications

Association of yeast Upf1p with direct substrates of the NMD pathway

Association of yeast Upf1p with direct substrates of the NMD pathway

Distinct class of putative “non-conserved” promoters in humans: Comparative studies of alternative promoters of human and mouse genes

Multiple facets of junD gene expression are atypical among AP-1 family members

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