Poison Exon Splicing Regulates a Coordinated Network of SR Protein Expression during Differentiation and Tumorigenesis

Splicing alterations in healthy aging and disease

“…This is likely due to many factors: (i) although most SFs are expressed ubiquitously, with the notable exception of most neuronal SFs, they do exhibit tissue‐specificity in their targets. There is evidence for tissue specific regulation of gene expression and splicing (Wang, Wu, et al, 2018) and therefore SFs could display distinct functions across aged tissues; (ii) from a technical standpoint, this collection of studies utilized differing techniques to measure gene expression, used differential computational tools, and had different definitions of young and old ages; (iii) variability across studies may result from differential aging rate of tissues (i.e., Is a 60‐year old heart as “old” as a 60‐year old brain), as well as from cell composition of tissues used (i.e., some tissues are composed of more homogenous cell populations than others); (iv) many SFs themselves are alternatively spliced, often resulting in production of non‐coding transcripts, a mechanism used to regulate SF protein levels (Lareau et al, 2007; Lareau & Brenner, 2015; Leclair et al, 2020). Therefore, while the transcript level could be unchanged or changing, this might not fully reflect the final protein levels.…”

Truncated RNA-binding protein production by DUX4-induced systemic inhibition of nonsense-mediated RNA decay

“…As an example of this phenomenon, we observed that exogenous expression of the truncated splicing factor SRSF3-TR causes a significant increase in the level of the corresponding aberrant SRSF3 RNA. Splicing factors are known to regulate and coordinate their expression via various forms of autoregulation (Konigs et al, 2020; Leclair et al, 2020; Muller-McNicoll, Rossbach, Hui, & Medenbach, 2019). Overexpression of full-length SRSF3 leads to a reduction in the level of normal SRSF3 transcript while at the same time activating the production of aberrant SRSF3 RNA that gets degraded by NMD in a balancing act mechanism that prevents SRSF3 accumulation (Jumaa & Nielsen, 1997).…”

Noncanonical functions of the serine‐arginine‐rich splicing factor (SR) family of proteins in development and disease

“…[ 50 ] Interestingly, all members of the SR protein family themselves contain a highly conserved PTC, also called a poison exon, allowing them to regulate their own degradation, and hence expression levels. [ 40,55,56 ] In addition to regulating itself, SRSF3 also regulates the stability of SRSF2, SRSF5 and SRSF7 transcripts. [ 40 ]…”

“…In general, SR protein expression varies between cell types but it is often higher in undifferentiated cells and decreases as differentiation progresses. [ 56 ] In some cases, such as the cardiac and neural lineages, the differences in expression levels can be explained by enhanced inclusion of their own poison exon leading to NMD in the more differentiated cells. Thus, one challenge in deciphering the precise roles of individual SR proteins in stem cell differentiation is that they act in a cross‐regulatory network by controlling their expression through NMD via their own ultraconserved poison exon sequences.…”

“…Thus, one challenge in deciphering the precise roles of individual SR proteins in stem cell differentiation is that they act in a cross‐regulatory network by controlling their expression through NMD via their own ultraconserved poison exon sequences. [ 56 ] Evolutionary, all prototypical SR proteins share a single ancient origin, [ 8 ] and interestingly, more distantly related SR proteins tend to positively regulate each other, while more closely related SR proteins compete by negatively regulating each other's expression. [ 56 ] An SR protein network may be particularly important for brain function as SRSF3, SRSF6, SRSF7 and SRSF9 have been implicated in neurological disorders by regulating splicing of Tau, a microtubule associated protein with multiple functions required for neuronal formation and health.…”