Regulation of CHD2 expression by a long noncoding RNA is essential for mammalian development

Long noncoding RNAs (lncRNAs) are enriched in regions flanking transcription- and chromatin-associated genes, but the functional importance of such co-location events is largely unclear. Chromodomain helicase DNA binding protein 2 (Chd2) is chromatin remodeller with various reported functions in cell differentiation and DNA damage response. Heterozygous mutations in human CHD2 have been implicated in epilepsy, neurodevelopmental delay, and intellectual disability. Here we show that Chaser, a highly conserved long noncoding RNA transcribed from a region in close proximity to the transcription start site of Chd2 and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd2 expression levels. Loss of Chaser in mice leads to substantially increased levels of Chd2 mRNA and protein in the embryo and in adult tissues, early postnatal lethality in homozygous animals, and severe growth retardation in heterozygotes. Mechanistically, over-production of Chd2 induced by loss of Chaser leads to increased transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaser production represses Chd2 expression solely in cis, and the phenotypic consequences of Chaser loss are rescued when Chd2 is perturbed as well. Targeting Chaser is thus a potentially viable strategy for increasing CHD2 levels in haploinsufficient individuals. Overall design: RNA-seq of mEFs from different genetic background with RNA-seq, RIP-seq of CHD2 in Neuro2a cells, Pol2 on mEFs and mESCs