Enhancer RNA-driven looping enhances the transcription of the long noncoding RNA DHRS4-AS1, a controller of the DHRS4 gene cluster

Sci Rep. 2016 Feb 11;6:20961. doi: 10.1038/srep20961.


The human DHRS4 gene cluster consists of DHRS4 and two immediately downstream homologous genes, DHRS4L2 and DHRS4L1, generated by evolutionarily gene-duplication events. We previously demonstrated that a head-to-head natural antisense transcript (NAT) of DHRS4, denoted DHRS4-AS1, regulates all three genes of the DHRS4 gene cluster. However, it is puzzling that DHRS4L2 and DHRS4L1 did not evolve their own specific NATs to regulate themselves, as it seems both have retained sequences highly homologous to DHRS4-AS1. In a search of the DHRS4-AS1 region for nearby enhancers, we identified an enhancer located 13.8 kb downstream of the DHRS4-AS1 transcriptional start site. We further showed, by using a chromosome conformation capture (3C) assay, that this enhancer is capable of physically interacting with the DHRS4-AS1 promoter through chromosomal looping. The enhancer produced an eRNA, termed AS1eRNA, that enhanced DHRS4-AS1 transcription by mediating the spatial interactions of the enhancer and DHRS4-AS1 promoter in cooperation with RNA polymerase II and p300/CBP. Moreover, the distributions of activating acetyl-H3 and H3K4me3 modifications were found to be greater at the DHRS4-AS1 promoter than at the homologous duplicated regions. We propose that AS1eRNA-driven DNA looping and activating histone modifications promote the expression of DHRS4-AS1 to economically control the DHRS4 gene cluster.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Base Sequence
  • Cell Line
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation*
  • Hep G2 Cells
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Multigene Family*
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / genetics*
  • Oxidoreductases / metabolism
  • Promoter Regions, Genetic
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • RNA, Antisense / genetics
  • RNA, Antisense / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Signal Transduction
  • Transcription Initiation Site
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism


  • Histones
  • Protein Isoforms
  • RNA, Antisense
  • RNA, Long Noncoding
  • Oxidoreductases
  • DHRS4 protein, human
  • p300-CBP Transcription Factors
  • RNA Polymerase II