SRA

We identified a germline heterozygous loss-of-function mutation in ZCCHC8, an RNA exosome targeting component, in a family with autosomal dominant pulmonary fibrosis and telomerase RNA insufficiency. To understand the in vivo consequences of Zcchc8 loss, we targeted the gene locus. Zccchc8+/- showed no significant phenotypes but Zcchc8-/- mice showed severe neurodevelopmental defects and died early in adulthood by 60 days. To understand the causes underlying this neurodevelopmental defect, we performed RNAseq on embryonic mouse heads (including the brain). We found no significant changes in gene expression in Zcchc8+/- relative to Zcchc8+/+ embryos. In contrast, Zcchc8-/- mice had a skewed signature marked by upregulation of low abundant transcripts and short, single exon genes including replication-dependent histones. These genes, like telomerase RNA, had extended 3' ends consistent with ZCCHC8 playing a role in both telomerase RNA as well as histone gene post-transcriptional processing. Overall design: We performed RNAseq on heads (including brains) of embryos with these genotypes: Zcchc8+/+ (n=5), Zcchc8+/- (n=3) and Zcchc8-/- (n=6) that were harvested on day E12.5.