A Conserved Nuclear Element with a Role in Mammalian Gene Regulation

Abstract

Mammalian genomes contain numerous fragments of DNA that are derived from inactivated transposable elements. The accumulation and persistence of these elements is generally attributed to transposase activity rather than through possession or acquisition of a function of value to the host genome. Here we describe such a repetitive element, named ALF (forannexin VILINE-2fragment), comprising 130 bp of DNA derived from a LINE-2 sequence, which functions as a potent T-cell-specific silencer. The expansion of the DNA database arising as a result of the human genome sequencing project enabled us to identify ALF in, or close to, several well characterized genes including those for annexin VI, interleukin-4 and protein kinase C-beta. A systematic analysis of the entire LINE-2 sequence revealed that ALF, and not other regions of the LINE-2 sequence, was especially highly represented in the human genome. Acquisition of a function by this repetitive element may explain its abundance. These data show that a conserved fragment of an interspersed nuclear element has the potential to modulate gene expression, a discovery that has broad implications for the way in which we view so-called 'junk' DNA and our understanding of eukaryotic gene regulation.

A novel mode of enhancer evolution: The Tal1 stem cell enhancer recruited a MIR element to specifically boost its activity

“…However, very little is known about a possible role for transposable elements in the evolution of distal regulatory elements, a situation most likely explained by the relative ease of identifying promoters compared to distal regulatory elements. Despite this, a few examples of repetitive DNA gaining specific functions as distal regulatory elements have emerged where transposable elements have been shown to act as enhancers (Hambor et al 1993;Bejerano et al 2006;Santangelo et al 2007) and silencers (Donnelly et al 1999). Indeed, a recent report suggests that many exapted nonexonic elements may be preferentially involved in distal cis-regulation (Lowe et al 2007) Given the recent reports that 16% of eutherian-specific conserved noncoding sequence is derived from transposable elements (Mikkelsen et al 2007) and that a proportion of these exapted noncoding elements are under strong purifying selection (Lowe et al 2007), it is becoming increasingly clear that repetitive elements have been a driving force in carving the landscape of the human genome.…”

“…To date, very few of these elements have been functionally validated. However, there have been specific instances where repetitive elements have been shown to function as silencers (Donnelly et al 1999) and polyadenylation or alternative splice sites (Medstrand et al 2005), although experimental validation has so far been largely restricted to those elements derived from the more recent, primate-specific Alu family of repeats. However, a role for more ancient repeats in gene regulation is also now emerging with the discovery of two neuronal enhancers that are derived from ancient short interspersed nucleotide elements (SINE) retroposons (Bejerano et al 2006;Santangelo et al 2007).…”

Functional analysis of the human annexin A5 gene promoter: a downstream DNA element and an upstream long terminal repeat regulate transcription

“…The prospect that human annexin A5 transcription is subject to retroviral repressor element(s) (Figure 3) is a concrete example of symbiotic co-evolution at the molecular level, and a potentially major modulator during cell cycling, tissue differentiation or changed cellular environment. Interestingly, a LINE-2 element with transcriptionally repressive components has been characterized in the upstream promoter of annexin A6 [27], with which annexin A5 shared its most recent common ancestor [43]. A complete murine endogenous retroviral element (MuERV)-L resides in mouse annexin A5 intron 4 [20], and a rare Alu subfamily retroposon at bp k452 to k627 in the human annexin A1 promoter [24], further testify to the involvement of retroposons in the structural evolution of annexin genes.…”

“…Regulatory regions have been partially characterized in only three other annexin genes, i.e. annexin A1 in pigeon [22] and human [23][24][25][26] and those for human annexins A6 [26,27] and A7 [28]. Annexins A5 and A6 shared their most recent common ancestor 500-700 million years ago [20], yet they retain no apparent homology in noncoding regions.…”

Classification of common conserved sequences in mammalian intergenic regions

“…This suggests that sequences derived from TEs may play a significant role in mammalian gene regulation (14,30). Although TEs that can be recognized by RepeatMasker, which typically means >50% similarity to a TE consensus in a sequence of more than 50 nucleotides, were masked before the construction of hits (4), shorter sequences of apparent TE origin were not excluded.…”