DBRWD3 Regulates Tissue Overgrowth and Ectopic Gene Expression Caused by Polycomb Group Mutations.

Hsueh-Tzu Shih,Hsiu-Hsiang Lee,Paul-Chen Hsieh,June-Tai Wu,Kwei-Yan Liu,Wei-Yu Chen,Yu-Chen Tsai,Pang-Hung Hsu,Zong-Siou Shih,Kuan-Lin Kuo,Yi-Jyun Chen,Shih-Peng Chan,Ya-Wen Liu,Kuo-How Huang,Gregory P Copenhaver

doi:10.1371/journal.pgen.1006262

Abstract

To maintain a particular cell fate, a unique set of genes should be expressed while another set is repressed. One way to repress gene expression is through Polycomb group (PcG) proteins that compact chromatin into a silent configuration. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to developmental defects and malignant tumors. Little is known about the molecular nature of ectopic gene expression; especially what differentiates expression of a given gene in the orthotopic tissue (orthotopic expression) and the ectopic expression of the same gene due to PcG mutations. Here we present that ectopic gene expression in PcG mutant cells specifically requires dBRWD3, a negative regulator of HIRA/Yemanuclein (YEM)-mediated histone variant H3.3 deposition. dBRWD3 mutations suppress both the ectopic gene expression and aberrant tissue overgrowth in PcG mutants through a YEM-dependent mechanism. Our findings identified dBRWD3 as a critical regulator that is uniquely required for ectopic gene expression and aberrant tissue overgrowth caused by PcG mutations.

Highlights

The eukaryotic genome is packaged in a macromolecular complex termed chromatin
Our results indicate that the inactivation of dBRWD3 or promotion of H3.3 deposition may selectively suppress ectopic gene expression and tumorigenesis driven by mutations in Polycomb group (PcG)
We previously showed that histone repressor A (HIRA)/YEM activity is negatively regulated by dBRWD3 (Bromodomain and WD repeat-containing protein 3) [11], which adds a second layer of complex regulation to H3.3 deposition

Summary

Introduction

The eukaryotic genome is packaged in a macromolecular complex termed chromatin. Chromatin is composed of DNA, RNA, histones, and non-histone proteins. We previously showed that HIRA/YEM activity is negatively regulated by dBRWD3 (Bromodomain and WD repeat-containing protein 3) [11], which adds a second layer of complex regulation to H3.3 deposition. Dendritic arborization of peripheral neurons and photoreceptor development are disrupted in dBRWD3 mutants. These phenotypes are effectively suppressed by mutations in yem or H3.3, indicating that dBRWD3 functions largely through restricting YEM-dependent H3.3 deposition [11]. It remains unknown where in the genome this regulation of H3.3 deposition takes place and how it affects transcription

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Conclusion