Deletion at an 1q24 locus reveals a critical role of long noncoding RNA DNM3OS in skeletal development

Ting-Ting Yu,Qiu-Fan Xu,Chen Liu,Si-Yang Li,Hui-Jie Huang,Shen Yue,Jennifer A Roggenbuck,Steven Y Cheng,Lei Shao,Sarah Dugan,Huai-Ze Liu,Xiao-Tong Liu,Betsy A Hirsch

doi:10.1186/s13578-021-00559-8

Abstract

BackgroundSkeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. However, the role of long non-coding RNAs (lncRNAs), a class of crucial epigenetic regulatory molecules, has been under explored in skeletal biology.ResultsHere we report a young patient with short stature, hypothalamic dysfunction and mild macrocephaly, who carries a maternally inherited 690 kb deletion at Chr.1q24.2 encompassing a noncoding RNA gene, DNM3OS, embedded on the opposite strand in an intron of the DYNAMIN 3 (DNM3) gene. We show that lncRNA DNM3OS sustains the proliferation of chondrocytes independent of two co-cistronic microRNAs miR-199a and miR-214. We further show that nerve growth factor (NGF), a known factor of chondrocyte growth, is a key target of DNM3OS-mediated control of chondrocyte proliferation.ConclusionsThis work demonstrates that DNM3OS is essential for preventing premature differentiation of chondrocytes required for bone growth through endochondral ossification.

Highlights

Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways
These data suggest that DNM3OS carries an essential function that accounts for the roles of chromosomal 1q23-1q25 interval in skeletal development and the ablation of miR-214 in mice is not sufficient to cause phenotype that resembles any aspect of the partial Noonan syndrome manifestation seen in the proband, it partakes in the regulation of skeletal growth via the Ras pathway
The size and color of the dots represent the enriched gene number and the range of p values, respectively. d Genes associated with chondrogenesis that are up- or down-regulated in full length Dnm3os (FL) and DKO transfected primary articular chondrocytes. e Verification of LncRNA-DNM3 opposite strand (Dnm3os) regulated genes in (d) by RT-qPCR in chondrocytes transfected by RK5, FL, DKO and miR214 individually

Summary

Introduction

Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. One of them is the RAS oncogene and the mitogen-activated protein kinase (MAPK) signaling pathway, which integrate signals from several growth factors such as growth hormone (GH), fibroblast growth factors (FGFs) and epithelial growth factor (EGF) [8,9,10,11]. Mutations in this pathway underpin a number of genetic syndromes that are collectively termed ‘rasopathies’; these

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