Bromodomain Inhibition of the Coactivators CBP/EP300 Facilitate Cellular Reprogramming

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2019 Apr 10

PMID 30962627

Citations 43

Authors

Ayyub Ebrahimi

Kenan Sevinc

Gulben Gurhan Sevinc

Adam P Cribbs

Martin Philpott

Firat Uyulur

Tunc Morova

James E Dunford

Sencer Goklemez

Sule Ari

Udo Oppermann

Tamer T Onder

Affiliations

Soon will be listed here.

Abstract

Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.

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