Genomic gems: SINE RNAs regulate mRNA production

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Mammalian short interspersed elements (SINEs) are abundant retrotransposons that have long been considered junk DNA; however, RNAs transcribed from mouse B2 and human Alu SINEs have recently been found to control mRNA production at multiple levels. Upon cell stress B2 and Alu RNAs bind RNA polymerase II (Pol II) and repress transcription of some protein-encoding genes. Bi-directional transcription of a B2 SINE establishes a boundary that places the growth hormone locus in a permissive chromatin state during mouse development. Alu RNAs embedded in Pol II transcripts can promote evolution and proteome diversity through exonization via alternative splicing. Given the diverse means by which SINE encoded RNAs impact production of mRNAs, this genomic junk is proving to contain hidden gems.

Introduction

Generating an mRNA is a complex process with numerous points of control. The enzyme Pol II synthesizes mRNA transcripts in eukaryotes, and a number of additional general transcription factors (GTFs) are necessary for transcription to occur [1]. Transcription is both positively and negatively regulated by a host of factors including promoter-specific activators and repressors, chromatin and histone associated proteins, and co-regulator complexes that can bridge the general transcription machinery to regulatory proteins [1, 2, 3, 4]. The transcription reaction undergoes a series of steps including formation of the preinitiation complex at the promoters of genes, initiation of transcription, promoter escape and transcript elongation. Pre-mRNA splicing is another key regulatory step in generating a mature mRNA. Splicing occurs co-transcriptionally and patterns of alternative splicing can be affected by transcription [5, 6]. Although the majority of factors that are known to regulate transcription or alternative splicing are proteins, a comparably small number of non-coding RNAs (ncRNAs) have also been found to function as regulators of these processes [7].

The mobile retroelements Alu, B1 and B2 are part of a family known as short interspersed elements (SINEs). An astounding 11% of the human genome is composed of Alu SINEs [8]. By comparison, the mouse genome contains approximately 550 000 B1 and 350 000 B2 SINEs [9, 10]. SINEs, which have an internal RNA polymerase III (Pol III) promoter, encode a small RNA and propagate non-autonomously by using the L1 long interspersed element (LINE) machinery to incorporate into their host genome [11]. SINE elements are ubiquitous, and are located throughout their host genome from intergenic regions to being embedded in protein-encoding genes [12, 13, 14]. Consequently, many SINEs are also transcribed as part of larger Pol II transcripts.

Historically, SINEs were thought of as ‘junk DNA’, useful primarily for determining phylogenetic relationships between organisms and probing mammalian speciation [15, 16, 17]. However, a number of labs found Pol III SINE transcripts to increase under a variety of cell stresses [18, 19, 20, 21, 22]. Furthermore, bioinformatic analysis showed thousands of SINEs were present in constrained nonexonic elements, suggesting that SINEs serve a biological and perhaps evolutionary role [23].

What was long thought of as genomic junk is turning out to contain hidden treasure; SINEs have been found to possess diverse and evolutionarily important biological functions from altering gene expression, to localizing mRNAs, to serving as mobile Pol II promoters [24, 25, 26, 27]. This review will concentrate on recent studies investigating the regulation of mRNA production by RNAs transcribed from Alu, B1, and B2 SINEs.

Section snippets

B2 and Alu RNAs act as transregulators of mRNA transcription

Pol III transcribes Alu RNA, B2 RNA, and B1 RNA in a regulated fashion (Figure 1a) [28, 29, 30]. Human Alu RNA is ∼300 nt in length and is composed of two 7SL derived arms linked by an A-rich region [31]. The ∼140 nt mouse B1 RNA is similar to the arms of Alu RNA [32]. The ∼180 nt B2 RNA originated from tRNA and is not related to Alu and B1 RNA in sequence or secondary structure [33]. The observation that upon heat shock, and other cellular stresses, levels of Pol III transcribed Alu, B1, and B2

A B2 SINE serves as a boundary element to regulate transcription during organogenesis

Recently, a B2 SINE was found to regulate mRNA transcription in a developmental and tissue-specific manner [41••] (Figure 2). The murine growth hormone (GH) locus has differential expression profiles during the development of the pituitary gland. In specific cells of the pituitary, the GH gene transitions from being silenced to being transcriptionally active at embryonic stage 17.5. Fluorescence in situ hybridization experiments found that the GH gene localization changed from regions of

Alu RNA contained in primary mRNA can change patterns of alternative splicing

Genomic complexity is increased by the ability to produce multiple different mature mRNAs from a single primary mRNA through alternative splicing. Bioinformatic studies suggest that greater than 70% of human genes are alternatively spliced [44, 45]. Recent studies have found that Alu RNAs embedded within Pol II transcripts can influence alternative splicing. Alu SINEs are thought to be present in over 5% of alternatively spliced internal exonic regions, hence a large portion of mature mRNAs

Conclusion

It is becoming apparent that SINE encoded RNAs can perform vital roles in regulating transcription and mRNA splicing, thereby controlling processes as diverse as the stress response, development, and proteome diversity. During cell stress, Pol III transcribed Alu and B2 RNAs repress mRNA transcription. Transcription of B2 RNA can establish a boundary and thereby regulate gene expression via controlling the state of chromatin in a developmentally specific manner. Embedded Alu RNAs can affect

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work was supported by a Public Health Service grant (R01 GM068414) from the National Institute of General Medical Sciences.

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