Functional Conservation of LncRNA JPX Despite Sequence and Structural Divergence

J Mol Biol. 2020 Jan 17;432(2):283-300. doi: 10.1016/j.jmb.2019.09.002. Epub 2019 Sep 10.

Abstract

Long noncoding RNAs (lncRNAs) have been identified in all eukaryotes and are most abundant in the human genome. However, the functional importance and mechanisms of action for human lncRNAs are largely unknown. Using comparative sequence, structural, and functional analyses, we characterize the evolution and molecular function of human lncRNA JPX. We find that human JPX and its mouse homolog, lncRNA Jpx, have deep divergence in their nucleotide sequences and RNA secondary structures. Despite such differences, both lncRNAs demonstrate robust binding to CTCF, a protein that is central to Jpx's role in X chromosome inactivation. In addition, our functional rescue experiment using Jpx-deletion mutant cells shows that human JPX can functionally complement the loss of Jpx in mouse embryonic stem cells. Our findings support a model for functional conservation of lncRNAs independent from sequence and structural divergence. This study provides mechanistic insight into the evolution of lncRNA function.

Keywords: Comparative analysis; Long noncoding RNA; Molecular evolution; Sequence–structure–function; X chromosome inactivation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CCCTC-Binding Factor / genetics*
  • Evolution, Molecular*
  • Genome, Human / genetics
  • Humans
  • Mice
  • Nucleic Acid Conformation
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / ultrastructure
  • X Chromosome Inactivation / genetics*

Substances

  • CCCTC-Binding Factor
  • CTCF protein, human
  • RNA, Long Noncoding