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Alterations in gene processing impact gene expression

Di Croce, Luciano (CRG)

Life & Medical Sciences

Irimia, Manuel (UPF)

Life & Medical Sciences

Cells use special protein complex, like Polycomb Repressive Complex, to turn genes off. PRC2 does this by adding chemical marks to proteins around which DNA is wrapped. Polycomb can form two different complexes that behave differently, but how cells control these forms has been unclear.In our research, we studied how cells switch between these different PRC2 forms using a special mechanism called alternative splicing—a process cells use to make many types of proteins from the same gene. We discovered a new type of PRC2 created by this splicing, which surprisingly affects stem cells differentiation.This helps us understand how cells precisely control their genes, which is crucial for development and health.

The PRC2 component SUZ12 is present in two alternative splicing isoforms depending on the inclusion or exclusion of SUZ12 fourth exon - represented by squares on both sides. On the one hand, the ancestral isoform mainly acts in a monomeric complex – symbolized by the red semicircle – that methylates nucleosomes on vast portions of the genome. On the other hand, the novel isoform is able to focus PRC2 activity on gene promoters, by favoring PRC2 dimerization. The exon involved in this splicing event is constitutively included in non-eutherian mammals, including marsupials (represented by a kangaroo) and only becomes alternative in placental mammals (represented by a deer), where the two isoforms are coexpressed and contribute to modify chromatin.


REFERENCE

- Arecco N, Mocavini I, Blanco E, Ballaré C, Libman E, Bonnal S, Irimia M & Di Croce L 2024, 'Alternative splicing decouples local from global PRC2 activity', Molecular Cell, 84 - 6.