LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes

PLoS Genet. 2015 Dec 3;11(12):e1005680. doi: 10.1371/journal.pgen.1005680. eCollection 2015 Dec.


Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA), LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA-HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Chondrogenesis / genetics*
  • Epigenesis, Genetic / genetics
  • Extremities / growth & development
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Limb Buds / growth & development
  • Mesoderm / growth & development
  • Mice
  • RNA, Long Noncoding / biosynthesis
  • RNA, Long Noncoding / genetics*
  • p120 GTPase Activating Protein / biosynthesis
  • p120 GTPase Activating Protein / genetics*


  • RNA, Long Noncoding
  • p120 GTPase Activating Protein

Associated data

  • GEO/GSE70986