Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Proc Natl Acad Sci U S A. 2015 Dec 1;112(48):14840-5. doi: 10.1073/pnas.1506760112. Epub 2015 Nov 17.


RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome-wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that pre-mRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate.

Keywords: H3.3; RNA polymerase II; alternative splicing; chromatin; transcription elongation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Hyaluronan Receptors / biosynthesis
  • Hyaluronan Receptors / genetics
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • RNA Precursors / biosynthesis*
  • RNA Precursors / genetics
  • RNA Splicing / physiology*
  • Transcription Elongation, Genetic / physiology*


  • CD44 protein, human
  • Histones
  • Hyaluronan Receptors
  • RNA Precursors
  • RNA Polymerase II

Associated data

  • GEO/GSE69307