Regulation of CHD2 expression by the Chaserr long noncoding RNA gene is essential for viability

Aviv Rom, Liliya Melamed, Noa Gil, Micah Jonathan Goldrich, Rotem Kadir, Matan Golan, Inbal Biton, Rotem Ben-Tov Perry and Igor Ulitsky ()
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Aviv Rom: Weizmann Institute of Science
Liliya Melamed: Weizmann Institute of Science
Noa Gil: Weizmann Institute of Science
Micah Jonathan Goldrich: Weizmann Institute of Science
Rotem Kadir: Ben-Gurion University of the Negev
Matan Golan: Weizmann Institute of Science
Inbal Biton: Weizmann Institute of Science
Rotem Ben-Tov Perry: Weizmann Institute of Science
Igor Ulitsky: Weizmann Institute of Science

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Chromodomain helicase DNA binding protein 2 (Chd2) is a chromatin remodeller implicated in neurological disease. Here we show that Chaserr, a highly conserved long noncoding RNA transcribed from a region near 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 Chaserr in mice leads to early postnatal lethality in homozygous mice, and severe growth retardation in heterozygotes. Mechanistically, loss of Chaserr leads to substantially increased Chd2 mRNA and protein levels, which in turn lead to transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaserr production represses Chd2 expression solely in cis, and that the phenotypic consequences of Chaserr loss are rescued when Chd2 is perturbed as well. Targeting Chaserr is thus a potential strategy for increasing CHD2 levels in haploinsufficient individuals.

Date: 2019
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DOI: 10.1038/s41467-019-13075-8

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