The RNA binding protein ZFP36L2 displays tissue-selective mRNA targeting in mice

ZFP36L2 (zinc finger protein 36 like 2, C3H type-ZFP) is an RNA-binding protein targeting transcripts rich in adenine-uridine elements (AREs). Previous transcriptomic analysis suggested that ZFP36L2 displays a distinct transcript preference or 'specific activity'. However, this analysis was restricted to a few tissues. Here, using experimental data in multiple tissues we detected a remarkable transcript selectivity depending on the tissue. Given that ZFP36L2 accelerates the degradation of specific ARE-transcripts upon binding, we obtained differential expression transcriptomic data on a Zfp36l2 knock-out mouse model to delve into the mechanisms governing this tissue-specific targeting. Transcriptomic analyzes of up-regulated ARE-transcripts in six tissues, lung, liver, bone marrow, spleen, kidney, and ovary of the Zfp36l2-deficient mouse confirmed that there is high tissue preference in ZFP36L2 targets. We observed only one common up-regulated gene, Apol11b, among these six different tissues. However, we do observe common trends, specifically an enrichment in protein coding genes in the up-regulated genes, consistent with these RBP primarily targeting genes on their 3' UTRs. Interestingly, we observed a significant increase in the proportion of IgV (immunoglobulin) genes being up-regulated. We further performed eCLIP (Enhanced Cross-Linking&ImmunoPreciptation) on a mouse cell line to explore potential binding sites of ZFP36L2. AU-Rich Element score (AREscore) analysis revealed enrichment in both up-regulated genes and eCLIP peaks, although some differences were observed in flanking residue composition. Our findings provide new insights into the intricate regulatory network orchestrated by ZFP36L2, opening avenues for exploring its potential roles in different tissues.