Regulatory functions of long noncoding RNAs in the nervous system

CHASERR is a long non-coding RNA highly conserved across vertebrates. It has been shown that CHASERR regulates the levels of expression of the Chromodomain Helicase DNA binding protein 2 (CHD2) gene. CHASERR terminates ~2 kb upstream of the CHD2 transcription start site and reduces its levels. Loss of CHASERR results in a ~60% increase in CHD2 mRNA levels and an equally or occasionally more substantial increase in CHD2 protein levels.

CHD2 mutations is implicated in neuronal dysfunction. In humans, CHD2 haploinsufficiency is associated with neurodevelopmental delay, intellectual disability, epilepsy, and behavioral problems. In mice, partial loss of Chd2 affects neurogenesis in the embryonic cerebral cortex. In human stem cells, it affects neuronal differentiation, and loss of a single Chd2 copy leads to deficits in neuron proliferation and a shift in neuronal excitability.

The regulatory circuit formed by Chaserr-Chd2 is highly important for postnatal survival, as Chaserr^–/– mice are not viable. This strong phenotype is mainly driven by increase in CHD2 levels, as Chd2 loss-of-function can rescue the lethality caused by loss of Chaserr. Therapeutic approaches based on inhibition of CHASERR can be potentially relevant for boosting CHD2 levels in the brain of individuals haploinsufficient for this gene.

We are targeting Chaserr transiently to see how it affect Chd2 expression by different approaches including injections of modified antisense oligos (ASOs) into different brain regions, which can be potentially used as a bona fide therapeutic approach.