HP1γ binding pre-mRNA intronic repeats modulates RNA splicing decisions

• Published in: EMBO reports Vol. 22; no. 9; pp. e52320 - n/a
• Main Authors: Rachez, Christophe, Legendre, Rachel, Costallat, Mickaël, Varet, Hugo, Yi, Jia, Kornobis, Etienne, Muchardt, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2021; Springer Nature B.V; EMBO Press; John Wiley and Sons Inc
• Subjects: Alternative splicing; Binding; Cbx3; Chromatin; DNA-directed RNA polymerase; EMBO09; EMBO36; Enrichment; Exons; Gene silencing; Genomes; Heterochromatin; HP1; Introns; Life Sciences; Proteins; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; Splice junctions; Splicing; Transcription; HP1; splicing; RNA; chromatin; Cbx3; splicing Subject Categories Chromatin; Transcription & Genomics; RNA Biology
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.202052320

HP1 proteins are best known as markers of heterochromatin and gene silencing. Yet, they are also RNA-binding proteins and the HP1γ/CBX3 family member is present on transcribed genes together with RNA polymerase II, where it regulates co-transcriptional processes such as alternative splicing. To gain insight in the role of the RNA-binding activity of HP1γ in transcriptionally active chromatin, we have captured and analysed RNAs associated with this protein. We find that HP1γ is specifically targeted to hexameric RNA motifs and coincidentally transposable elements of the SINE family. As these elements are abundant in introns, while essentially absent from exons, the HP1γ RNA association tethers unspliced pre-mRNA to chromatin via the intronic regions and limits the usage of intronic cryptic splice sites. Thus, our data unveil novel determinants in the relationship between chromatin and co-transcriptional splicing. Synopsis HP1γ associates with pre-mRNA preferentially at specific repeat motifs enriched in introns, and this association affects co-transcriptional processes such as alternative splicing. HP1γ is associated genome-wide with introns of chromatin-enriched pre-messenger RNA. HP1γ-associated RNA is enriched in CACACA and GAGAGA repeat motifs. A subset of intragenic sense SINE repeats containing CACACA motifs are targeted by HP1γ. Association of HP1γ with intronic RNA affects alternative splicing and the occurrence of cryptic splice junctions. Graphical Abstract HP1γ associates with pre-mRNA preferentially at specific repeat motifs enriched in introns, and this association affects co-transcriptional processes such as alternative splicing.