Chromatin-bound RB targets promoters, enhancers, and CTCF-bound loci and is redistributed by cell-cycle progression

Ioannis Sanidas; Hanjun Lee; Purva H Rumde; Gaylor Boulay; Robert Morris; Gabriel Golczer; Marcelo Stanzione; Soroush Hajizadeh; Jun Zhong; Meagan B Ryan; Ryan B Corcoran; Benjamin J Drapkin; Miguel N Rivera; Nicholas J Dyson; Michael S Lawrence

doi:10.1016/j.molcel.2022.07.014

Chromatin-bound RB targets promoters, enhancers, and CTCF-bound loci and is redistributed by cell-cycle progression

Mol Cell. 2022 Sep 15;82(18):3333-3349.e9. doi: 10.1016/j.molcel.2022.07.014. Epub 2022 Aug 17.

Authors

Affiliations

¹ Massachusetts General Hospital Cancer Center, Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA.
² Massachusetts General Hospital Cancer Center, Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
³ Massachusetts General Hospital Cancer Center, Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
⁴ Massachusetts General Hospital Cancer Center, Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA; UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
⁵ Massachusetts General Hospital Cancer Center, Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA. Electronic address: [email protected].
⁶ Massachusetts General Hospital Cancer Center, Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Electronic address: [email protected].

Abstract

The interaction of RB with chromatin is key to understanding its molecular functions. Here, for first time, we identify the full spectrum of chromatin-bound RB. Rather than exclusively binding promoters, as is often described, RB targets three fundamentally different types of loci (promoters, enhancers, and insulators), which are largely distinguishable by the mutually exclusive presence of E2F1, c-Jun, and CTCF. While E2F/DP facilitates RB association with promoters, AP-1 recruits RB to enhancers. Although phosphorylation in CDK sites is often portrayed as releasing RB from chromatin, we show that the cell cycle redistributes RB so that it enriches at promoters in G1 and at non-promoter sites in cycling cells. RB-bound promoters include the classic E2F-targets and are similar between lineages, but RB-bound enhancers associate with different categories of genes and vary between cell types. Thus, RB has a well-preserved role controlling E2F in G1, and it targets cell-type-specific enhancers and CTCF sites when cells enter S-phase.

Keywords: AP-1; CTCF; E2F; PanChIP; RB phosphorylation; RB-bound enhancers; RB-bound promoters; cell-cycle regulation; regulation of RB activity; retinoblastoma protein.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Chromatin* / genetics
E2F Transcription Factors / genetics
E2F Transcription Factors / metabolism
E2F1 Transcription Factor / genetics
E2F1 Transcription Factor / metabolism
Promoter Regions, Genetic
Retinoblastoma Protein* / genetics
Retinoblastoma Protein* / metabolism
Transcription Factor AP-1 / genetics

Substances

Cell Cycle Proteins
Chromatin
E2F Transcription Factors
E2F1 Transcription Factor
Retinoblastoma Protein
Transcription Factor AP-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding