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.
Subject(s)
Cell Cycle/genetics , Cell Differentiation/genetics , Drosophila Proteins/genetics , Polycomb-Group Proteins/genetics , Transcription Factors/genetics , Animals , Cell Cycle Proteins/biosynthesis , Cell Cycle Proteins/genetics , Chromatin/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Drosophila Proteins/biosynthesis , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Eye/growth & development , Eye/metabolism , Gene Expression Regulation, Developmental , Histone Chaperones/biosynthesis , Histone Chaperones/genetics , Histones/genetics , Imaginal Discs/growth & development , Imaginal Discs/metabolism , Mutation , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Polycomb-Group Proteins/biosynthesis , Transcription Factors/biosynthesisABSTRACT
Many causal mutations of intellectual disability have been found in genes involved in epigenetic regulations. Replication-independent deposition of the histone H3.3 variant by the HIRA complex is a prominent nucleosome replacement mechanism affecting gene transcription, especially in postmitotic neurons. However, how HIRA-mediated H3.3 deposition is regulated in these cells remains unclear. Here, we report that dBRWD3, the Drosophila ortholog of the intellectual disability gene BRWD3, regulates gene expression through H3.3, HIRA, and its associated chaperone Yemanuclein (YEM), the fly ortholog of mammalian Ubinuclein1. In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation. Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations. Our work thus establishes a previously unknown negative regulation of H3.3 and advances our understanding of BRWD3-dependent intellectual disability.