The long and the short of TRF2 in neurogenesis

Abstract

Gene expression patterns change dramatically during neuronal development. Proliferating cells, including neural stem cells (NSCs), express telomere repeat-binding factor 2 (TRF2), a nuclear protein that associates with telomeric proteins, DNA, and RNA telomeres. In NSCs TRF2 also binds to the transcription regulator REST to facilitate repression of numerous neuron-specific genes, thereby keeping the NSCs in a selfrenewing state. Upon neuronal differentiation, TRF2 levels decline, REST-regulated neuronal genes are derepressed, and a short isoform of TRF2 arises (TRF2-S) which localizes in the cytoplasm, associates with different subsets of proteins and transcripts, and mobilizes axonal G-rich mRNAs. We recently identified two RNA-binding proteins, HNRNPH1 and H2 (referred to jointly as HNRNPH due to their high homology), which mediate the alternative splicing of an exon required for the expression of full-length TRF2. As HNRNPH levels decline during neurogenesis, TRF2 abundance decreases and TRF2-S accumulates. Here, we discuss the shared and unique functions of TRF2 and TRF2-S, the distinct subcellular compartment in which each isoform resides, the subsets of proteins and nucleic acids with which each interacts, and the functional consequences of these ribonucleoprotein interactions. This paradigm illustrates the dynamic mechanisms through which splicing regulation by factors like HNRNPH enable distinct protein functions as cells adapt to developmental programs such as neurogenesis.

Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells

“…Using stainings for TRF2 and telomere FISH, we found that some telomeres are preferentially located within ELCS and their immediate proximity. Further evidence supports the idea that telomere-associated proteins are likely to contribute to the regulation of cellular proliferative capacity (Blasco, 2002, Grammatikakis et al., 2016). Previous studies have also shown that telomeres are associated to lamins and lamin-associated proteins such as Lap2, and are rich in epigenetic modifications, as we confirm here for H3K9me3 (Gonzalo and Eissenberg, 2016).…”

Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation

“…The HNRNPH1 and HNRNPH2 proteins have similar function in regulation of pre‐mRNAs splicing; in particular, they are both involved in neuronal cell differentiation by regulating alternative splicing . A study in rat cortical neurons showed that although HNRNPH2 had a slightly lower effect than HNRNPH1, both paralogs acted similarly in controlling splicing of Trf2 through promoting the longer splice variant which inhibited neurogenesis .…”

Shelterin components modulate nucleic acids condensation and phase separation in the context of telomeric DNA

“…The interaction between TERRA and TRF2 has been proposed to facilitate heterochromatin formation, while TERRA depletion leads to an increase in TIFs (59). Intriguingly, a splice-variant of TRF2 lacking the linker and DBD (similar to TRF2 ΔC ) co-localizes with neuronal granules, ribonuclear biomolecular condensates that facilitate the transport of mRNAs in axons (60, 61). Based on our work here, one interpretation of this observation is that while the shorter TRF2 splice variant loses its ability to interact with telomeres it retains non-specific binding affinity for RNA, possibly via interactions within its basic N-terminus domain.…”