Splicing Isoforms Associated with TGFβ-Induced Myofibroblast Activation

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ABSTRACT Myofibroblast differentiation is a key process in developmental biology and involved in numerous physiopathology. The gene expression program orchestrating fibroblast to myofibroblast differentiation, as well as its recapitulation by TGFβ stimulation in vitro , is relatively well characterized. Intriguingly, it is known that the splicing isoform EDA+FN1 is a marker and driver of myofibroblast differentiation, but the alternative splicing landscape of myofibroblast is unknown. Here, we performed a high-throughput transcriptomic approach by RNA-Seq in a primary skin fibroblast line and uncover more than 250 splicing isoforms associated with TGFβ-induced myofibroblasts using two different bioinformatic pipelines. This splicing profile highlights a distinct layer of regulation when compared to the global gene expression profile of myofibroblasts. A 5 alternative splicing event (ASE) signature [ ACTN1- 19A/19B; COL5A1 -64A/64B; COL6A3 exon 4; FLNA exon 30 and TPM1 -6a/6b] was further validated by ddPCR and AS-PCR and retrieved in publicly available RNA-Seq datasets describing other TGFβ-stimulated lung and skin fibroblasts. Surprisingly, TGFβ does not induce an EDA+FN1 splicing shift, although it stimulates global fibronectin expression. Thus, we conclude that the 5 ASEs signature may be used as putative universal myofibroblast markers and be of functional significance to myofibroblast formation and biology.

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