Chromatin is the structure that makes it possible to compact the genetic material of cells within their nucleus, it is also a key element in the regulation of gene expression in the form of messenger RNA. HP1 proteins are associated with chromatin and are characteristic markers of heterochromatin, the repressed form of chromatin.

One of these proteins, the HP1gamma isoform, is associated with transcriptionally active genes. On these genes, it has an impact on RNA splicing, the process that leads to the maturation of pre-messenger RNAs into mature messenger RNAs.

Christophe Rachez, Mickael Costallat and Christian Muchardt (B2A), and their collaborators, analyzed the mechanisms by which the factor HP1gamma modulates RNA splicing. Using a genome-wide approach, they showed that HP1gamma is associated with most RNAs detected within chromatin. The portions of RNAs associated with HP1gamma are enriched with repeated motifs of the CACACA consensus sequence which are found in particular in certain repeated elements of the genome of the SINE family. These motifs are abundant in introns, RNA regions eliminated during splicing, but on the other hand they are very little present in exons, RNA regions conserved during splicing and which therefore constitute mature messenger RNAs. The localization of these motifs suggests their involvement in the impact of HP1gamma on splicing.

According to this model, the association of HP1gamma with these motifs on the RNA allows the maintenance of pre-messenger RNAs within the chromatin for the activity of the splicing machinery. Mature RNAs lacking these motifs would then be released from the chromatin. HP1 gamma therefore modulates the appearance of alternative forms of messenger RNAs (alternative splicing), but also limits the appearance of aberrant splicing sites. This work highlights a new determinant in the relationship between chromatin and RNA splicing.

Figure: A. The association of HP1 with pre-messenger RNA (pre-mRNA) which occurs essentially via repeated motifs (red arrows) modulates the functionality of the RNA splicing machinery.

B. The absence of HP1 (bottom panel) increases the probability of detecting aberrant splicing sites (green dotted arrow) which lead to the appearance of "cryptic" exons (Exon 2').

Team lead by Christian Muchardt: Epigenetics and RNA metabolism in human diseases (B2A, UMR 8256)

Rachez, C., Legendre, R., Costallat, M., Varet, H., Yi, J., Kornobis, E., & Muchardt, C. (2021). HP1gamma binding pre-mRNA intronic repeats modulates RNA splicing decisions. EMBO Reports, e52320. https://doi.org/10.15252/embr.202052320