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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers
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Cdk9 and H2Bub1 signal to Clr6-CII/Rpd3S to suppress aberrant antisense transcription

Miriam Sansó1,2, Pabitra K Parua1, Daniel Pinto3

  • 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Nucleic Acids Research
|June 5, 2020
PubMed

Insights

Cyclin-dependent kinase 9 (Cdk9) and histone H2B mono-ubiquitylation (H2Bub1) cooperate to suppress unwanted gene transcription. Disrupting either pathway increases antisense transcription, while ablating both affects over half the genome.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Gene Regulation

Background:

  • Histone H2B mono-ubiquitylation (H2Bub1) and cyclin-dependent kinase 9 (Cdk9)-mediated Spt5 phosphorylation are co-transcriptional modifications crucial for RNA polymerase II (RNAPII) transcription.
  • The interplay between Cdk9 and H2Bub1 in regulating individual gene expression and antisense transcription remained largely unexplored.

Purpose of the Study:

  • To investigate the cooperative roles of Cdk9 and H2Bub1 in controlling intragenic antisense transcription.
  • To elucidate the genome-wide distribution and interdependence of H2Bub1 and phospho-Spt5.
  • To identify genetic interactions linking Cdk9, H2Bub1, and histone deacetylase Clr6-CII.

Main Methods:

  • Fission yeast genetics and molecular biology techniques.
  • Genome-wide analysis of histone modifications and transcription using ChIP-seq and RNA-seq.
  • Inhibition of Cdk9 activity and genetic ablation of H2Bub1.

Main Results:

  • Inhibition of Cdk9 or loss of H2Bub1 individually induced intragenic antisense transcription in approximately 10% of fission yeast genes.
  • Ablation of both Cdk9 and H2Bub1 pathways led to de-repression of antisense transcription across over half the genome.
  • H2Bub1 and phospho-Spt5 showed similar genome-wide distributions, enriched in coding regions and decreasing near the cleavage and polyadenylation signal (CPS).
  • Cdk9-dependent suppression of antisense transcription correlated with high H2Bub1 occupancy and promoter-proximal RNAPII pausing.
  • Combined Cdk9 inhibition and H2Bub1 loss impaired Clr6-CII recruitment, leading to decreased histone occupancy and increased acetylation within gene coding regions.

Conclusions:

  • Cdk9 and H2Bub1 function in a cooperative pathway to suppress aberrant intragenic antisense transcription.
  • This pathway links RNAPII transcription elongation regulation with the suppression of initiation.
  • Novel interactions between co-transcriptional histone modification pathways were uncovered, involving Cdk9, H2Bub1, and Clr6-CII.

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