# Age-dependent regulation of ELP1 exon 20 splicing in Familial Dysautonomia by RNA Polymerase II kinetics and chromatin structure

## TL;DR

This study explores how RNA Polymerase II and chromatin structure regulate ELP1 exon 20 splicing in Familial Dysautonomia, revealing age-dependent changes in splicing patterns.

## Contribution

The paper introduces a co-transcriptional model linking age-related chromatin modifications to splicing regulation in Familial Dysautonomia.

## Key findings

- A slow RNAPII mutant and chromatin-modifying chemicals induce ELP1 exon 20 skipping.
- Age-dependent decreases in RNAPII density and increases in repressive chromatin marks correlate with reduced exon inclusion.
- Demethylation of H3K27 increases RNAPII elongation and promotes exon inclusion in ELP1 and SMN2.

## Abstract

Familial Dysautonomia (FD) is a rare disease caused by ELP1 exon 20 skipping. Here we clarify the role of RNA Polymerase II (RNAPII) and chromatin on this splicing event. A slow RNAPII mutant and chromatin-modifying chemicals that reduce the rate of RNAPII elongation induce exon skipping whereas chemicals that create a more relaxed chromatin exon inclusion. In the brain of a mouse transgenic for the human FD-ELP1 we observed on this gene an age-dependent decrease in the RNAPII density profile that was most pronounced on the alternative exon, a robust increase in the repressive marks H3K27me3 and H3K9me3 and a decrease of H3K27Ac, together with a progressive reduction in ELP1 exon 20 inclusion level. In HEK 293T cells, selective drug-induced demethylation of H3K27 increased RNAPII elongation on ELP1 and SMN2, promoted the inclusion of the corresponding alternative exons, and, by RNA-sequencing analysis, induced changes in several alternative splicing events. These data suggest a co-transcriptional model of splicing regulation in which age-dependent changes in H3K27me3/Ac modify the rate of RNAPII elongation and affect processing of ELP1 alternative exon 20.