TY - JOUR
T1 - Regulation of CHD2 expression by the Chaserr long noncoding RNA gene is essential for viability
AU - Rom, Aviv
AU - Melamed, Liliya
AU - Gil, Noa
AU - Goldrich, Micah Jonathan
AU - Kadir, Rotem
AU - Golan, Matan
AU - Biton, Inbal
AU - Perry, Rotem Ben Tov
AU - Ulitsky, Igor
N1 - Funding Information:
We thank Noam Stern-Ginossar, Schraga Schwarz, Shalev Itzkovitz, Alena Shkumatava, Yaqub Hanna, Eran Meshorer, and Ulitsky lab members for helpful discussions and comments on the paper. Damari Golda, Haffner-Krausz Rebecca, and Maizenberg Alina for mouse transgenics. Ori Brenner for assistance with histopathology. Dana Hirsh and Raya Eilam for assistance with single-molecule FISH. This research was supported by the Israeli Centers for Research Excellence (1796/12); Israel Science Foundation (1242/14 and 1984/14); European Research Council project lincSAFARI; Nella and Leon Benoziyo Center for Neurological Disease; The Helen and Martin Kimmel Institute for Stem Cell Research; Lapon Raymond; the Abramson Family Center for Young Scientists. I.U. is incumbent of the Sygnet Career Development Chair for Bioinformatics.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/11/8
Y1 - 2019/11/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074690014&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-13075-8
DO - 10.1038/s41467-019-13075-8
M3 - Article
C2 - 31704914
AN - SCOPUS:85074690014
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5092
ER -
