Reciprocal regulation of hnRNP C and CELF2 through translation and transcription tunes splicing activity in T cells

Abstract

RNA binding proteins (RBPs) frequently regulate the expression of other RBPs in mammalian cells. Such cross-regulation has been proposed to be important to control networks of coordinated gene expression; however, much remains to be understood about how such networks of cross-regulation are established and what the functional consequence is of coordinated or reciprocal expression of RBPs. Here we demonstrate that the RBPs CELF2 and hnRNP C regulate the expression of each other, such that depletion of one results in reduced expression of the other. Specifically, we show that loss of hnRNP C reduces the transcription of CELF2 mRNA, while loss of CELF2 results in decreased efficiency of hnRNP C translation. We further demonstrate that this reciprocal regulation serves to fine tune the splicing patterns of many downstream target genes. Together, this work reveals new activities of hnRNP C and CELF2, provides insight into a previously unrecognized gene regulatory network, and demonstrates how cross-regulation of RBPs functions to shape the cellular transcriptome.

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma

“…In addition, MBNL1 was the second most important SF. CELF2 and MBNL1 share some downstream genes and were both expressed at low levels, which agrees with the results of a recent research on the reciprocal regulatory roles of CELF2 and other SF ( 38 ). Most intensive studies have suggested that AS is regulated in a combinatorial manner by several SFs, which can be either synergistic or antagonistic ( 39 ).…”

PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca2+/NFAT signaling

“…How exactly this is achieved is currently unknown. However, TcR-induced splicing has been shown to be highly dependent on CELF2 induction and binding to specific mRNA sites 17,35,42 , leading to the intriguing possibility that interactions between PRMT5 and CELF2 may contribute to selective splicing regulation of a group of transcripts required for activated T cell function.…”

The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

“…76 Similarly, Tra2-β1, a positive regulator of exon 7 splicing, turned out to be dispensable for inclusion of this exon in a Tra2-β1-deficient mouse model. 97,98 These observations are not entirely surprising given the redundancy and cross-regulation of splicing factors as, for example, observed for PTB, CELF2, and hnRNP C. 99-101…”

“…splicing, turned out to be dispensable for inclusion of this exon in a Tra2-β1-deficient mouse model. 97,98 These observations are not entirely surprising given the redundancy and crossregulation of splicing factors as, for example, observed for PTB, CELF2, and hnRNP C. [99][100][101] The discovery of the 15-nucleotide long ISS-N1 propelled the development of an antisense oligonucleotide (ASO)directed therapy for SMA. 89,102,103 Based on its strong inhibitory effect, ISS-N1 was dubbed as a master regulator of both splicing checkpoint and exon definition.…”