PCGF5 is required for neural differentiation of embryonic stem cells

Mingze Yao,Xueke Zhou,Jiajian Zhou,Ping Lai,Andrew P Hutchins,Jiao Li,Kaimeng Huang,Huating Wang,Guang Shi,Gongcheng Hu,Hongjie Yao,Hao Sun,Shixin Gong

doi:10.1038/s41467-018-03781-0

Abstract

Polycomb repressive complex 1 (PRC1) is an important regulator of gene expression and development. PRC1 contains the E3 ligases RING1A/B, which monoubiquitinate lysine 119 at histone H2A (H2AK119ub1), and has been sub-classified into six major complexes based on the presence of a PCGF subunit. Here, we report that PCGF5, one of six PCGF paralogs, is an important requirement in the differentiation of mouse embryonic stem cells (mESCs) towards a neural cell fate. Although PCGF5 is not required for mESC self-renewal, its loss blocks mESC neural differentiation by activating the SMAD2/TGF-β signaling pathway. PCGF5 loss-of-function impairs the reduction of H2AK119ub1 and H3K27me3 around neural specific genes and keeps them repressed. Our results suggest that PCGF5 might function as both a repressor for SMAD2/TGF-β signaling pathway and a facilitator for neural differentiation. Together, our findings reveal a critical context-specific function for PCGF5 in directing PRC1 to control cell fate.

Highlights

Polycomb repressive complex 1 (PRC1) is an important regulator of gene expression and development
By screening epigenetic factors that are important for neural differentiation of human ESCs from an expression array analysis, we identified TET2, PCGF4 and PCGF5 as upregulated in human neural stem cells compared with hESCs (Fig. 1a)
We focused on studying the role of PCGF5 in hESCs and mouse embryonic stem cells (mESCs) during neural differentiation, reasoning that PCGF5 might be important in mediating ESC neural differentiation

Summary

Introduction

Polycomb repressive complex 1 (PRC1) is an important regulator of gene expression and development. Our results suggest that PCGF5 might function as both a repressor for SMAD2/TGF-β signaling pathway and a facilitator for neural differentiation. PCGF5 is not required for mESC self-renewal, its loss blocks neural differentiation by activating SMAD2 phosphorylation and the TGF-β signaling pathway. PCGF5 loss-of-function results in reductions of H2AK119ub[1] and H3K27me[3] at the promoters of TGF-β target genes (such as Nodal, Lefty[1], Lefty2), upregulation of pSMAD2, during neural differentiation, leading to dysfunction of TGF-β signaling pathway, and a consequent blockage towards a neural cell fate. PCGF5 is recruited to repressed genes, and binds to active genes during neural differentiation, suggesting PCGF5 may function as both a repressor for SMAD2/TGF-β signaling pathway and a facilitator for neural differentiation. This study reveals a critical context-specific function and mechanism for PCGF5PRC1 in controlling neural differentiation of mESCs

Methods

Results

Conclusion