Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape

Prajwal C. Boddu, Abhishek K. Gupta, Rahul Roy, Bárbara De La Peña Avalos, Anne Olazabal-Herrero, Nils Neuenkirchen, Joshua T. Zimmer, Namrata S. Chandhok, Darren King, Yasuhito Nannya, Seishi Ogawa, Haifan Lin, Matthew D. Simon, Eloise Dray, Gary M. Kupfer, Amit Verma, Karla M. Neugebauer, Manoj M. Pillai

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)1475-1495.e18
JournalMolecular Cell
Volume84
Issue number8
DOIs
StatePublished - Apr 18 2024

Keywords

  • DNA damage response
  • R-loops
  • RNA polymerase II
  • SF3B1
  • Sin3/HDAC
  • U2AF1
  • WDR5
  • co-transcriptional splicing
  • spliceosome
  • transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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