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

Aviv Rom,Igor Ulitsky,Inbal Biton,Matan Golan,Rotem Kadir,Rotem Ben-Tov Perry,Liliya Melamed,Micah Jonathan Goldrich,Noa Gil

doi:10.1038/s41467-019-13075-8

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.

Highlights

Chromodomain helicase DNA binding protein 2 (Chd2) is a chromatin remodeller implicated in neurological disease
By using single-molecule RNA FISH, we found that the RNA product of Chaserr is mostly localized in the nucleus, in proximity to the Chd[2] site of transcription, and subcellular fractionation shows that it is enriched in the chromatin fraction (Fig. 1b and Supplementary Fig. 1c)
We show that under conditions of excess levels of CHD2 protein, this TTS-proximal occupancy is associated with transcriptional interference on downstream neighbors of highly expressed genes, especially when the intergenic regions between them are short (Figs. 4e–g, 5a, b)

Summary

Introduction

Chromodomain helicase DNA binding protein 2 (Chd2) is a chromatin remodeller implicated in neurological disease. We show that Chaserr, a highly conserved long noncoding RNA transcribed from a region near the transcription start site of Chd[2] and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd[2] expression levels. Loss of Chaserr leads to substantially increased Chd[2] mRNA and protein levels, which in turn lead to transcriptional interference by inhibiting promoters found downstream of highly expressed genes. Chromodomain Helicase DNA Binding Protein 2 (Chd2) gene encodes an ATP-dependent chromatin-remodeling enzyme, which together with CHD1 belongs to subfamily I of the chromodomain helicase DNA-binding (CHD) protein family Members of this subfamily are characterized by two chromodomains located in the N-terminal region and a centrally located SNF2-like ATPase domain[7], and facilitate disassembly, eviction, sliding, and spacing of nucleosomes[8]. Heterozygotes with this mutation show increased postnatal mortality at days 1-4, and in the long term they exhibit growth retardation, shorter life spans, and altered morphology in various organs

Methods

Results

Conclusion