Do human transposable element small RNAs serve primarily as genome defenders or genome regulators?

It is currently thought that small RNA (sRNA) based repression mechanisms are primarily employed to mitigate the mutagenic threat posed by the activity of transposable elements (TEs). This can be achieved by the sRNA guided processing of TE transcripts via Dicer-dependent (e.g., siRNA) or Dicer-independent (e.g., piRNA) mechanisms. For example, potentially active human L1 elements are silenced by mRNA cleavage induced by element encoded siRNAs, leading to a negative correlation between element mRNA and siRNA levels. On the other hand, there is emerging evidence that TE derived sRNAs can also be used to regulate the host genome. Here, we evaluated these two hypotheses for human TEs by comparing the levels of TE derived mRNA and TE sRNA across six tissues. The genome defense hypothesis predicts a negative correlation between TE mRNA and TE sRNA levels, whereas the genome regulatory hypothesis predicts a positive correlation. On average, TE mRNA and TE sRNA levels are positively correlated across human tissues. These correlations are higher than seen for human genes or for randomly permuted control data sets. Overall, Alu subfamilies show the highest positive correlations of element mRNA and sRNA levels across tissues, although a few of the youngest, and potentially most active, Alu subfamilies do show negative correlations. Thus, Alu derived sRNAs may be related to both genome regulation and genome defense. These results are inconsistent with a simple model whereby TE derived sRNAs reduce levels of standing TE mRNA via transcript cleavage, and suggest that human cells efficiently process TE transcripts into sRNA based on the available message levels. This may point to a widespread role for processed TE transcripts in genome regulation or to alternative roles of TE-to-sRNA processing including the mitigation of TE transcript cytotoxicity.