Transposable elements can drive genome evolution, but their enhanced activity is detrimental to the host and therefore must be tightly regulated1. The piwi-interacting small RNAs (piRNAs) pathway is critically important for transposable element regulation, by inducing transcriptional silencing or post-transcriptional decay of mRNAs2. Here, we show that piRNAs and piRNA biogenesis components regulate pre-mRNA splicing of P transposable element transcripts in vivo, leading to the production of the non-transposase-encoding mature mRNA isoform in germ cells. Unexpectedly, we show that the piRNA pathway components do not act to reduce P-element transposon transcript levels during P-M hybrid dysgenesis, a syndrome that affects germline development in Drosophila3,4. Instead, splicing regulation is mechanistically achieved in concert with piRNA-mediated changes to repressive chromatin states, and relies on the function of the Piwi-piRNA complex proteins Asterix/Gtsf15–7 and Panoramix/Silencio8,9, as well as Heterochromatin Protein 1a (Su(var)205/HP1a). Furthermore, we show that this machinery, together with the piRNA Flamenco cluster10, not only controls the accumulation of Gypsy retrotransposon transcripts11 but also regulates splicing of Gypsy mRNAs in cultured ovarian somatic cells, a process required for the production of infectious particles that can lead to heritable transposition events12,13. Our findings identify splicing regulation as a new role and essential function for the Piwi pathway in protecting the genome against transposon mobility, and provide a model system for studying the role of chromatin structure in modulating alternative splicing during development.
Highlights d De novo Pitx1 expression defines tumor-propagating SCC cells d PITX1 governs a feed-forward circuit that enables TPCrenewal and clonal expansion d PITX1 function represses KLF4-dependent squamous differentiation d Pitx1 expression and function are restricted by KLF4 activity
SUMMARY T cell expression of sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) enables T cell exit from lymph nodes (LNs) into lymph, while endothelial S1PR1 expression regulates vascular permeability. Drugs targeting S1PR1 treat autoimmune disease by trapping pathogenic T cells within LNs, but they have adverse cardiovascular side effects. In homeostasis, the transporter SPNS2 supplies lymph S1P and enables T cell exit, while the transporter MFSD2B supplies most blood S1P and supports vascular function. It is unknown whether SPNS2 remains necessary to supply lymph S1P during an immune response, or whether in inflammation other compensatory transporters are upregulated. Here, using a model of dermal inflammation, we demonstrate that SPNS2 supplies the S1P that guides T cells out of LNs with an ongoing immune response. Furthermore, deletion of Spns2 is protective in a mouse model of multiple sclerosis. These results support the therapeutic potential of SPNS2 inhibitors to achieve spatially specific modulation of S1P signaling.
SummaryThe signaling lipid sphingosine 1‐phosphate (S1P) plays key roles in many physiological processes. In the immune system, S1P's best‐described function is to draw cells out of tissues into circulation. Here, we will review models of S1P distribution in the thymus, lymph nodes, spleen, and nonlymphoid tissues. These models have been challenging to construct, because of the lack of tools to map lipid gradients. Nonetheless, evidence to date suggests that S1P distribution is exquisitely tightly controlled, and that concentrations of signaling‐available S1P cannot be predicted by standard rules of thumb. The fine regulation of S1P gradients may explain how S1P can simultaneously direct multiple cell movements both between tissues and circulation and within tissues. It may also make it feasible to develop drugs that enable spatially specific modulation of S1P signaling.
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