Dynamic site-specific recruitment of RBP2 by pocket protein p130 modulates H3K4 methylation on E2F-responsive promoters

Nucleic Acids Res. 2018 Jan 9;46(1):174-188. doi: 10.1093/nar/gkx961.

Abstract

The Histone 3 lysine 4 methylation (H3K4me3) mark closely correlates with active transcription. E2F-responsive promoters display dynamic changes in H3K4 methylation during the course of cell cycle progression. However, how and when these marks are reset, is not known. Here we show that the retinoblastoma binding protein RBP2/KDM5A, capable of removing tri-methylation marks on H3K4, associates with the E2F4 transcription factor via the pocket protein-p130-in a cell-cycle-stage specific manner. The association of RBP2 with p130 is LxCxE motif dependent. RNAi experiments reveal that p130 recruits RBP2 to E2F-responsive promoters in early G1 phase to bring about H3K4 demethylation and gene repression. A point mutation in LxCxE motif of RBP2 renders it incapable of p130-interaction and hence, repression of E2F-regulated gene promoters. We also examine how RBP2 may be recruited to non-E2F responsive promoters. Our studies provide insight into how the chromatin landscape needs to be adjusted rapidly and periodically during cell-cycle progression, concomitantly with temporal transcription, to bring about expression/repression of specific gene sets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cells, Cultured
  • E2F Transcription Factors / metabolism*
  • E2F4 Transcription Factor / metabolism
  • G1 Phase / genetics
  • HeLa Cells
  • Histones / metabolism*
  • Humans
  • Methylation
  • Mice
  • Mutation
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • RNA Interference
  • Retinoblastoma-Binding Protein 2 / genetics
  • Retinoblastoma-Binding Protein 2 / metabolism*
  • Retinoblastoma-Like Protein p130 / genetics
  • Retinoblastoma-Like Protein p130 / metabolism*
  • Retinol-Binding Proteins, Cellular / genetics
  • Retinol-Binding Proteins, Cellular / metabolism*

Substances

  • E2F Transcription Factors
  • E2F4 Transcription Factor
  • E2F4 protein, human
  • Histones
  • RBL2 protein, human
  • RBP2 protein, human
  • Retinoblastoma-Like Protein p130
  • Retinol-Binding Proteins, Cellular
  • histone H3 trimethyl Lys4
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2