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

Long noncoding RNAs are now realized to function in various biological processes via multiple, and as of yet not fully understood, modes of action. 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. These fusion transcripts are exported to the cytoplasm and translated to produce full-length CHD2 proteins. They are expressed endogenously, albeit at low levels, and are induced in activated neurons. Deletion of these conserved regions in mice mimics the effects of the ASO, leading to increased CHD2 levels, altered chromatin accessibility and altered neuronal responses. Perinatal introduction of the ASO into the brains of Chd2+/– mice up-regulates CHD2 expression and alleviates behavioral phenotypes caused by CHD2 haploinsufficiency, providing a therapeutic route to CHD2 haploinsufficiency. The concept of targeting upstream genes with ASOs to induce transcript fusion can be extended to other gene pairs.