RNA polymerase II at histone genes predicts outcome in human cancer.

in Science (New York, N.Y.) by Steven Henikoff, Ye Zheng, Ronald M Paranal, Yiling Xu, Jacob E Greene, Jorja G Henikoff, Zachary R Russell, Frank Szulzewsky, H Nayanga Thirimanne, Sita Kugel, Eric C Holland, Kami Ahmad

TLDR

  • The study finds that cancer cells often have elevated levels of RNA polymerase II, which drives the production of histones and contributes to cancer progression.

Abstract

Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how hypertranscription might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)-cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide in FFPE sections. We demonstrate global RNAPII elevations in mouse gliomas and assorted human tumors in small clinical samples and discover regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at S-phase-dependent histone genes correlated with WHO grade in meningiomas, accurately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneuploidy in cancer, with general implications for precision oncology.

Overview

  • The study focuses on understanding the role of hypertranscription in human cancer, particularly in genome-wide mapping of RNA polymerase II (RNAPII) in formalin-fixed paraffin-embedded (FFPE) sections.
  • The researchers demonstrate global elevations in RNAPII in mouse gliomas and human tumors, as well as regional elevations corresponding to de novo HER2 amplifications.
  • The primary objective is to understand how histone gene hypertranscription drives overproliferation and aneuploidy in cancer, with implications for precision oncology.

Comparative Analysis & Findings

  • The study finds global elevations in RNAPII in mouse gliomas and assorted human tumors, suggesting a common mechanism in cancer.
  • Regional elevations corresponding to de novo HER2 amplifications are also identified, indicating a specific genomic event that may drive cancer progression.
  • RNAPII occupancy at S-phase-dependent histone genes correlates with WHO grade in meningiomas and accurately predicts rapid recurrence

Implications and Future Directions

  • The findings suggest that histone gene hypertranscription drives overproliferation and aneuploidy in cancer, highlighting the importance of histone production in S-phase progression.
  • Future studies could investigate the mechanistic links between histone gene hypertranscription and aneuploidy, as well as the role of histone gene hypertranscription in other types of cancer.
  • The results have general implications for precision oncology, as identifying elevated histone gene activity could indicate potential therapeutic targets for cancer treatment
Read Full Article