Inducible fusion with the CHASERR long noncoding RNA transcript upregulates haploinsufficient CHD2 expression

CHASERR is a long noncoding RNA conserved throughout vertebrates, located immediately upstream of the promoter of the CHD2 gene. CHD2 haploinsufficiency leads to a neurodevelopmental disorder that includes epilepsy and intellectual disability.

Homozygous loss of CHASERR promoter leads to embryonic lethality in mice, and heterozygous deletions lead to pleiotropic phenotypes in mice and a recently characterized syndromic human developmental disorder. Short highly conserved sequence motifs are present in the last exon of CHASERR and blocking them with antisense oligonucleotides (ASOs) up-regulates CHD2 expression. Here, we decipher the mechanism of action of these ASOs and show that they stimulate the formation of a fusion transcript connecting the first four exons of CHASERR with exons 2–39 of CHD2.