Transposon control as a checkpoint for tissue regeneration

Abstract

Tissue regeneration requires precise temporal control of cellular processes such as inflammatory signaling, chromatin remodeling and proliferation. The combination of these processes forms a unique microenvironment permissive to the expression, and potential mobilization of, transposable elements (TEs). Here, we develop the hypothesis that TE activation creates a barrier to tissue repair that must be overcome to achieve successful regeneration. We discuss how uncontrolled TE activity may impede tissue restoration and review mechanisms by which TE activity may be controlled during regeneration. We posit that the diversification and co-evolution of TEs and host control mechanisms may contribute to the wide variation in regenerative competency across tissues and species.

Keywords: Inflammation; Proliferation; Regenerative biology; Stem cells; Transposable elements.

Fig. 1.

Generalized timeline of known processes required for regeneration. Tissue regeneration can be broadly divided into three phases: wound signaling, stem/progenitor cell activation and clonal expansion, and cellular differentiation and morphogenesis. Phase I: wound signaling is characterized by the release of pro-inflammatory cytokines into the injured microenvironment. Phase II: pro-inflammatory signals trigger resident stem or progenitor cells (SCs) to exit quiescence and re-enter the cell cycle. SCs undergo rapid proliferation to repopulate lost tissues. Concurrently, pro-inflammatory signals decrease and anti-inflammatory signals increase. Phase III: inflammation and proliferation continue to decline as nascent daughter cells differentiate and integrate into existing healthy tissues, restoring functional cell-cell connections.

Fig. 2.

The regeneration environment is conducive to transposable element (TE) activity. (1) Injury-induced signals are released from dying cells that recruit leukocytes to the injury site. (2) Inflammatory signals induce resident stem cell activation, resulting in changes to chromatin accessibility and gene expression. (2′) Inflammatory signals trigger immune-specific transcription factors to bind TE promoters. (3) TEs ‘sense’ the dynamic cellular environment and begin to be expressed and/or activated. (4) TE mRNA translocates to the cytoplasm for translation and/or reverse transcription (RT). (5) Class I products re-enter the nucleus and ‘copy’ themselves into a new genomic locus, whereas (5′) Class II products re-enter the nucleus and ‘cut and paste’ into a new locus. (6) Transposition results in DNA damage, which inhibits DNA replication. (7) TE-encoded products and DNA damage signals activate the host intracellular innate immune response. (8) TE-induced inflammation could propagate an inflammatory feedback loop.

Fig. 3.

Known small RNA (sRNA) pathways involved in transposable element (TE) repression. (A) piRNA pathway: piRNAs precursors are transcribed from piRNA clusters then translocate to the cytoplasm where they undergo processing and are amplified through the ping-pong pathway by Piwi pathway proteins (e.g. Aub, Piwi and Ago3). Once processed, piRNAs bind TE sequences via sequence complementarity to inhibit TE translation or translocate into the nucleus to inhibit TE transcription. (B) miRNA pathway: pri-miRNA precursors form dsRNA hairpin structures, and are tails are cleaved by Drosha before translocation from the nucleus. In the cytoplasm, double-stranded miRNAs are processed by Dicer and loaded into the Ago/RISC complex as single-stranded miRNAs that can then mediate TE mRNA degradation and translation inhibition. (C) Endo-siRNA pathway: endo-siRNAs can be generated from repetitive genomic loci, including TEs, and are processed by the same machinery as miRNAs. (D) tRNA fragments: tRNA fragments are generated from repeat tRNA loci. Once in the cytoplasm, pre-tRNAs are processed by Dicer or angiogenin, which cleave the tRNA at different nucleotide sites to produce tRNA fragments (tRFs). Once mature, tRFs regulate TE translation and reverse transcription. Pathways are modeled primarily from Drosophila melanogaster and Mus musculus. RISC, RNA-induced silencing complex.

Fig. 4.

Hypothesis: transposable element (TE) repression is required for tissue regeneration. TE expression (magenta) increases shortly after injury (yellow), which results in TE-induced inflammatory signaling (purple). TEs retaining functional DNA and protein-coding sequences will attempt to transpose (blue) and, given sufficient time, accumulation of TE mutagenic activity would bypass the host cell ‘threshold’ (dotted line), disrupting homeostasis and forcing the cell to enter senescence. In response, host cells must deploy TE repression mechanisms (green) to limit TE activity. (A) Regeneratively competent organisms (e.g. planarian, zebrafish and axolotl) effectively deploy TE countermeasures, thereby limited TE activity to below threshold levels and allowing for successful regeneration (gray). (B) Less regeneratively competent organisms (e.g. humans, chickens and mice) cannot effectively limit TE mutagenic events and incur too many cellular deficits, leading to regeneration stall.