Small RNAs derived from lncRNA RNase MRP have gene-silencing activity

Post-transcriptional processing of some long noncoding RNAs (lncRNAs) reveals that they are a source of miRNAs. Researchers at the Albert Einstein College of Medicine show that the 268 nt non-coding RNA component of Mitochondrial RNA Processing endoribonuclease, (RNase MRP) is the source of at least two short (∼20nt) RNAs designated RMRP-S1, and RMRP-S2, that function as miRNAs. Point mutations in RNase MRP cause human Cartilage Hair Hypoplaisia (CHH), and several disease-causing mutations map to RMRP-S1 and -S2. SHAPE chemical probing identified two alternative secondary structures altered by disease mutations. RMRP-S1 and S2 are significantly reduced in two fibroblast cell lines and a B cell line derived from CHH patients. Tests of gene regulatory activity of RMRP-S1 and S2 identified over 900 genes that were significantly regulated, of which over 75% were down regulated, and 90% contained target sites with seed complements of RMRP-S1 and S2 predominantly in their 3′ UTRs. Pathway analysis identified regulated genes that function in skeletal development, hair development, and hematopoietic cell differentiation including PTCH2 and SOX4 among others, linked to major CHH phenotypes. Also, genes associated with alternative RNA splicing, cell proliferation and differentiation were highly targeted. Therefore, alterations RMRP-S1 and S2, caused by point mutations in RMRP, are strongly implicated in the molecular mechanism of CHH.

• Rogler LE, Kosmyna B, Moskowitz D, Bebawee R, Rahimzadeh J, Kutchko K, Laederach A, Notarangelo LD, Giliani S, Bouhassira E, Frenette P, Roy-Chowdhury J, Rogler CE. (2013) Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human Cartilage Hair Hypoplasia. Hum Mol Genet [Epub ahead of print]. [abstract]