RNA polymerase II at histone genes predicts outcome in human cancer
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.
Authors
- Frank Szulzewsky (ORCID: https://orcid.org/0000-0001-5710-9590)
- Ye Zheng (ORCID: https://orcid.org/0000-0002-8806-2761)
- Zachary R. Russell (ORCID: https://orcid.org/0009-0003-9659-6389)
- Steven Henikoff (ORCID: https://orcid.org/0000-0002-7621-8685)
- Yiling Xu (ORCID: https://orcid.org/0009-0000-8622-2066)
- Jorja G. Henikoff (ORCID: https://orcid.org/0000-0001-7670-5101)
- Sita Kugel (ORCID: https://orcid.org/0000-0001-7202-187X)
- Ronald M. Paranal (ORCID: https://orcid.org/0000-0002-4263-4621)
- Jacob E. Greene (ORCID: https://orcid.org/0000-0002-3016-7296)
- H. Nayanga Thirimanne (ORCID: https://orcid.org/0000-0002-8016-3031)
- Kami Ahmad (ORCID: https://orcid.org/0000-0001-8572-6182)
- Eric C. Holland (ORCID: https://orcid.org/0000-0002-3792-7120)
Institutions
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
Publication Details
- Journal
- Science
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1126/science.ads2169
- Citations
- 30
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 23.37
Funders
- Fred Hutchinson Cancer Research Center
- National Institutes of Health
- National Cancer Institute