Abstract
ABSTRACTThe pituitary-derived somatolactotrophe GH3 cells secrete both growth hormone (GH) and prolactin (PRL). We have found that the hnRNP L and L-like (LL) paralogs differentially regulate alternative splicing of genes in these cells. Here, we show that hnRNP L is essential for PRL only, but LL is essential for both PRL and GH production. Transcriptome-wide RNA sequencing (RNA-Seq) analysis indicates that they differentially control groups of hormone or hormone-related genes involved in hormone production/regulation at total transcript and alternative exon levels. Interestingly, hnRNP L also specifically binds and prevents the aberrant usage of a nonconserved CA-rich intron piece of Prl pre-mRNA transcripts, and many others involved in endocrine functions, to prevent mostly cryptic last exons and mRNA truncation. Essential for the full hnRNP L effect on specific exons is a proline-rich region that emerged during evolution in vertebrate hnRNP L only but not LL. Together, our data demonstrate that the hnRNP L and its paralog, LL, differentially control hormone gene expression programs at multiple levels, and hnRNP L in particular is critical for protecting the transcriptome from aberrant usage of intronic sequences. The multilevel differential control by hnRNPs likely tailors the transcriptome to help refine and safeguard the different gene expression programs for different hormones.
Highlights
The pituitary-derived somatolactotrophe GH3 cells secrete both growth hormone (GH) and prolactin (PRL)
We have found that heterogeneous ribonucleoproteins (hnRNPs) L and LL differentially regulate the alternative splicing of genes involved in hormone production in GH3 rat pituitary cells [28,29,30]
We show that the diverged hnRNP L and LL paralogs differentially control the production of PRL and GH hormones, as well as the transcript and alternative exon levels of many other genes involved in endocrine functions
Summary
The pituitary-derived somatolactotrophe GH3 cells secrete both growth hormone (GH) and prolactin (PRL). Of the many factors involved, the heterogeneous ribonucleoproteins (hnRNPs) are a family of abundant and critical players in the posttranscriptional processing of pre-mRNA transcripts [1, 2] They have evolved to about 30 members, including homologs or paralogs [3], for the tens of thousands of gene transcripts in vertebrates. The role of the different, paralogous, vertebrate hnRNPs in relation to specific cell functions and the accompanying gene expression programs remains largely unclear. Among their diverse functions, gene regulation at the transcript and exon levels in vertebrate, mammalian, systems has been well known [1, 3,4,5]. Elucidating distinct properties and transcript targets of hnRNP paralogs will help reveal the logic of their expansion and orchestration of the processing of particular mRNA targets in cell functions/diseases
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