Dataset Information

The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity.

ABSTRACT: Human L1 elements are non-LTR retrotransposons that comprise approximately 17% of the human genome. Their 5'-untranslated region (5'-UTR) serves as a promoter for L1 transcription. Now we find that transcription initiation sites are not restricted to nucleotide +1 but vary considerably in both downstream and upstream directions. Transcription initiating upstream explains additional nucleotides often seen between the 5'-target site duplication and the L1 start site. A higher frequency of G nucleotides observed upstream from the L1 can be explained by reverse transcription of the L1 RNA 5'-CAP, which is further supported by extra Gs seen for full-length HERV-W pseudogenes. We assayed 5'-UTR promoter activities for several full-length human L1 elements, and found that upstream flanking cellular sequences strongly influence the L1 5'-UTR promoter. These sequences either repress or enhance the L1 promoter activity. Therefore, the evolutionary success of a human L1 in producing progeny depends not only on the L1 itself, but also on its genomic integration site. The promoter mechanism of L1 is reminiscent of initiator (Inr) elements that are TATA-less promoters expressing several cellular genes. We suggest that the L1 5'-UTR is able to form an Inr element that reaches into upstream flanking sequence.

SUBMITTER: Lavie L

PROVIDER: S-EPMC525683 | biostudies-literature | 2004 Nov

REPOSITORIES: biostudies-literature

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The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity.

Lavie Laurence L Maldener Esther E Brouha Brook B Meese Eckart U EU Mayer Jens J

Genome research 20041101 11

Human L1 elements are non-LTR retrotransposons that comprise approximately 17% of the human genome. Their 5'-untranslated region (5'-UTR) serves as a promoter for L1 transcription. Now we find that transcription initiation sites are not restricted to nucleotide +1 but vary considerably in both downstream and upstream directions. Transcription initiating upstream explains additional nucleotides often seen between the 5'-target site duplication and the L1 start site. A higher frequency of G nucleo ...[more]

PMID: 15520289

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Project description:BackgroundClassically, models of DNA-transcription factor binding sites (TFBSs) have been based on relatively few known instances and have treated them as sites of fixed length using position weight matrices (PWMs). Various extensions to this model have been proposed, most of which take account of dependencies between the bases in the binding sites. However, some transcription factors are known to exhibit some flexibility and bind to DNA in more than one possible physical configuration. In some cases this variation is known to affect the function of binding sites. With the increasing volume of ChIP-seq data available it is now possible to investigate models that incorporate this flexibility. Previous work on variable length models has been constrained by: a focus on specific zinc finger proteins in yeast using restrictive models; a reliance on hand-crafted models for just one transcription factor at a time; and a lack of evaluation on realistically sized data sets.ResultsWe re-analysed binding sites from the TRANSFAC database and found motivating examples where our new variable length model provides a better fit. We analysed several ChIP-seq data sets with a novel motif search algorithm and compared the results to one of the best standard PWM finders and a recently developed alternative method for finding motifs of variable structure. All the methods performed comparably in held-out cross validation tests. Known motifs of variable structure were recovered for p53, Stat5a and Stat5b. In addition our method recovered a novel generalised version of an existing PWM for Sp1 that allows for variable length binding. This motif improved classification performance.ConclusionsWe have presented a new gapped PWM model for variable length DNA binding sites that is not too restrictive nor over-parameterised. Our comparison with existing tools shows that on average it does not have better predictive accuracy than existing methods. However, it does provide more interpretable models of motifs of variable structure that are suitable for follow-up structural studies. To our knowledge, we are the first to apply variable length motif models to eukaryotic ChIP-seq data sets and consequently the first to show their value in this domain. The results include a novel motif for the ubiquitous transcription factor Sp1.

Dataset Information

The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity.

Publications

The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity.

Similar Datasets

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