Journal Article

Distribution of alternative untranslated regions within the mRNA of the CELF1 splicing factor affects its expression

Sekrecki, Michal, Kajdasz, Arkadiusz, Niewiadomska, Daria, Sobczak, Krzysztof

2022

Overview

CUG-binding protein, ELAV-like Family Member 1 (CELF1) plays an important role during the development of different tissues, such as striated muscle and brain tissue. CELF1 is an RNA-binding protein that regulates RNA metabolism processes, e.g., alternative splicing, and antagonizes other RNA-binding proteins, such as Muscleblind -like proteins (MBNLs). Abnormal activity of both classes of proteins plays a crucial role in the pathogenesis of myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults. In this work, we show that alternative splicing of exons forming both the 5′ and 3′ untranslated regions (UTRs) of CELF1 mRNA is efficiently regulated during development and tissue differentiation and is disrupted in skeletal muscles in the context of DM1. Alternative splicing of the CELF1 5′UTR leads to translation of two potential protein isoforms that differ in the lengths of their N-terminal domains. We also show that the MBNL and CELF proteins regulate the distribution of mRNA splicing isoforms with different 5′UTRs and 3′UTRs and affect the CELF1 expression by changing its sensitivity to specific microRNAs or RNA-binding proteins. Together, our findings show the existence of different mechanisms of regulation of CELF1 expression through the distribution of various 5′ and 3′ UTR isoforms within CELF1 mRNA.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 3' Untranslated Regions / 5' Untranslated Regions / 631/337/1645 / 692/699/375/374 / Adult / Aged / Alternative Splicing / Animals / Binding Sites / CELF1 Protein - biosynthesis / CELF1 Protein - genetics / Chlorocebus aethiops / COS Cells / Dystrophy / Exons / Female / HeLa Cells / Humanities and Social Sciences / Humans / Isoforms / Male / Mice / Mice, Inbred C57BL / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / miRNA / mRNA / multidisciplinary / Muscle, Skeletal - metabolism / Muscles / Muscular Dystrophies - genetics / Muscular Dystrophies - metabolism / Muscular dystrophy / Myotonic dystrophy / Protein Biosynthesis / Protein Isoforms / Protein turnover / Proteins / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA-binding protein / Science / Science (multidisciplinary) / Skeletal muscle / Splicing factors / Young Adult