Publication Date

2018-12-04

Availability

Embargoed

Embargo Period

2020-12-03

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2018-11-09

First Committee Member

Joyce M. Slingerland

Second Committee Member

Ramin Shiekhattar

Third Committee Member

Maria E. Figueroa

Fourth Committee Member

Anthony J. Capobianco

Abstract

The Polycomb repressive complexes play diverse and essential roles in cell fate decisions, embryonic development, stem cell pluripotency, and gene regulation. There are two main Polycomb complexes in mammalian cells, Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). PRC1 can be further subdivided into canonical and non-canonical complexes depending on its composition (cPRC1 and ncPRC1). Historically, Polycomb complexes have been mostly associated with maintaining gene repression carried out by its histone-modifying and chromatin-remodeling capabilities. Specifically, PRC1 can catalyze mono-ubiquitination of histone H2A on lysine 119 while PRC2 trimethylates histone H3 on lysine 27. Both these histone marks are associated with maintenance of gene repression. In addition, both complexes have been demonstrated to modulate the chromatin landscape through its interactions at promoters and distal regulatory regions to repress transcription. However, increasing evidence indicates that specific PRC1 variants can be recruited to actively transcribed genes in multiple biological processes including stem cell differentiation and cancer. Notably, the function of PRC2 is extensively documented in multiple cancer types and agents targeting PRC2 subunits are currently ongoing in multiple clinical trials. However, the role of PRC1 in cancer is less well understood. We aimed to determine whether PRC1 plays a functional role in cancer development and progression. To this end, we first interrogated published patient datasets in to determine the genetic alterations of PRC1 subunits in all cancer types and found that PRC1 genes were highly amplified and overexpressed in breast cancers. Particularly, RNF2, encoding the core enzymatic PRC1 subunit RING1B, was amplified in 22% of diagnosed breast cancers. Genome-wide assays revealed that cPRC1 functionally associated with genes regulated by cell-type-specific key transcription factors, such as estrogen receptor and BRD4 in different breast cancer molecular subtypes. Unexpectedly, cPRC1 is also recruited to active enhancers and this recruitment is independent of RING1B enzymatic activity. We found that RING1B depletion regulated enhancer activity and gene transcription not only by promoting the expression of breast cancer oncogenes but also by regulating chromatin accessibility for oncogenic transcription factors. Finally, by analyzing public datasets, we show that concomitant recruitment of RING1B and cPRC1 to active enhancers occurs across multiple cancer types, highlighting an under-explored function of cPRC1 variants in regulating specific oncogenic transcriptional programs in cancer. These observations may have important implications in the development of cancer therapeutic agents targeting epigenetic complexes.

Keywords

polycomb; cancer; epigenetics; prc1; enhancers; super enhancers

Available for download on Thursday, December 03, 2020

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