Polak, P. & Domany, E. Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes. BMC Genomics 7, 133

Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100, Israel.
BMC Genomics (Impact Factor: 3.99). 02/2006; 7:133. DOI: 10.1186/1471-2164-7-133
Source: PubMed


The human genome contains over one million Alu repeat elements whose distribution is not uniform. While metabolism-related genes were shown to be enriched with Alu, in structural genes Alu elements are under-represented. Such observations led researchers to suggest that Alu elements were involved in gene regulation and were selected to be present in some genes and absent from others. This hypothesis is gaining strength due to findings that indicate involvement of Alu elements in a variety of functions; for example, Alu sequences were found to contain several functional transcription factor (TF) binding sites (BSs). We performed a search for new putative BSs on Alu elements, using a database of Position Specific Score Matrices (PSSMs). We searched consensus Alu sequences as well as specific Alu elements that appear on the 5 Kbp regions upstream to the transcription start site (TSS) of about 14000 genes.
We found that the upstream regions of the TSS are enriched with Alu elements, and the Alu consensus sequences contain dozens of putative BSs for TFs. Hence several TFs have Alu-associated BSs upstream of the TSS of many genes. For several TFs most of the putative BSs reside on Alu; a few of these were previously found and their association with Alu was also reported. In four cases the fact that the identified BSs resided on Alu went unnoticed, and we report this association for the first time. We found dozens of new putative BSs. Interestingly, many of the corresponding TFs are associated with early markers of development, even though the upstream regions of development-related genes are Alu-poor, compared with translational and protein biosynthesis related genes, which are Alu-rich. Finally, we found a correlation between the mouse B1 and human Alu densities within the corresponding upstream regions of orthologous genes.
We propose that evolution used transposable elements to insert TF binding motifs into promoter regions. We observed enrichment of biosynthesis genes with Alu-associated BSs of developmental TFs. Since development and cell proliferation (of which biosynthesis is an essential component) were proposed to be opposing processes, these TFs possibly play inhibitory roles, suppressing proliferation during differentiation.

Download full-text


Available from: Eytan Domany
  • Source
    • "Similarly, a large fraction of functional 217 genomic sites consists of primate-specific TEs derived from ERV1 (Wang, T. et al., 2007). In 218 addition, Alu and L2 elements contain TF binding motifs those expected to bind by TFs in 219 vivo (Johnson et al., 2006;Laperriere et al., 2007;Polak and Domany, 2006). Next, about 32% 220 of the binding sites detected in vivo for five TFs (ESR1, TP53, POU5F1, SOX2, and CTCF) 221 derived from multiple TE families (Bourque et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Human Genome Project revealed that almost half of the human genome consists of transposable elements (TEs), which are also abundant in non-human primates. Various studies have confirmed the roles of different TE families in primate evolution. TEs such as endogenous retroviruses (ERVs), long terminal repeats (LTRs), long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs) all have numerous effects on the primate genome, including genomic rearrangement, regulatory functions and epigenetic mechanisms. This review offers an overview of research on TEs, including our current understanding of their presence in modern primate lineages, their evolutionary origins, and their regulatory and modifying effects on primate as well as human genomes. The information provided here should be useful for the study of primate genomics.
    Full-text · Article · Jan 2016 · Genes & Genetic Systems
  • Source
    • "Therefore, within the 4th quartile group we could not find statistically significant association between the presence of the repeat elements or length and the number of miRNA sites (p-value = 0.15, Wilcoxon rank sum test). For some of these 3′UTRs, the repeat elements may explain the presence of other regulatory elements such as binding sites for DNA or RNA binding proteins [34,35]. A useful approach to interrogate element functionality relies on sequence conservation [36-38]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: miRNAs are a major class of regulators of gene expression in metazoans. By targeting cognate mRNAs, miRNAs are involved in regulating most, if not all, biological processes in different cell and tissue types. To better understand how this regulatory potential is allocated among different target gene sets, we carried out a detailed and systematic analysis of miRNA target sites distribution in the mouse genome. We used predicted conserved and non-conserved sites for 779 miRNAs in 3[prime] UTR of 18440 genes downloaded from TargetScan website. Our analysis reveals that 3[prime] UTRs of genes encoding regulatory proteins harbor significantly greater number of miRNA sites than those of non-regulatory, housekeeping and structural, genes. Analysis of miRNA sites for orthologous 3[prime]UTR's in 10 other species indicates that the regulatory genes were maintaining or accruing miRNA sites while non-regulatory genes gradually shed them in the course of evolution. Furthermore, we observed that 3[prime] UTR of genes with higher gene expression variability driven by their promoter sequence content are targeted by many more distinct miRNAs compared to genes with low transcriptional noise. Based on our results we envision a model, which we dubbed "selective inclusion", whereby non-regulatory genes with low transcription noise and stable expression profile lost their sites, while regulatory genes which endure higher transcription noise retained and gained new sites. This adaptation is consistent with the requirements that regulatory genes need to be tightly controlled in order to have precise and optimum protein level to properly function.
    Full-text · Article · Apr 2014 · BMC Evolutionary Biology
  • Source
    • "Alu elements are preferentially distributed in gene-rich regions and contain one-third of the total CpG dinucleotides in the human genome (Batzer and Deininger, 2002), as well as many putative transcription factor (TF) binding sites, which may increase their likelihood to either enhance or repress gene expression (Polak and Domany, 2006). Although Alu insertions can mutate functional units, these features have been suggested to reflect a distinct advantageous contribution of Alu elements to the transcriptional landscape of the human genome (Batzer and Deininger, 2002; Cordaux and Batzer, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The human genome contains approximately one million Alu repetitive elements comprising 10% of the genome, yet their functions are not well understood. Here, we show that Alu elements resemble enhancers. Alu elements are bound by two well-phased nucleosomes that contain histones bearing marks of active chromatin, and they show tissue-specific enrichment for the enhancer mark H3K4me1. A proportion of Alu elements were experimentally validated as bona fide active enhancers with an in vitro reporter assay. In addition, Hi-C data indicate that Alus show long-range interactions with gene promoters. We also find that Alus are generally more conserved when located in the proximal upstream region of genes. Their similarity to enhancers becomes more prominent with their age in the human genome, following a clear evolutionary continuum reminiscent of the evolutionary pattern of proto-genes. Therefore, we conclude that some Alu elements can function as enhancers and propose that many more may be proto-enhancers that serve as a repertoire for the de novo birth of enhancers.
    Full-text · Article · Apr 2014 · Cell Reports
Show more