Abstract
ATP-dependent chromatin remodelers control DNA access for transcription, recombination, and other processes. Acf1 (also known as BAZ1A in mammals) is a defining subunit of the conserved ISWI-family chromatin remodelers ACF and CHRAC, first purified over 15 years ago from Drosophila melanogaster embryos. Much is known about biochemical properties of ACF and CHRAC, which move nucleosomes in vitro and in vivo to establish ordered chromatin arrays. Genetic studies in yeast, flies and cultured human cells clearly implicate these complexes in transcriptional repression via control of chromatin structures. RNAi experiments in transformed mammalian cells in culture also implicate ACF and CHRAC in DNA damage checkpoints and double-strand break repair. However, their essential in vivo roles in mammals are unknown. Here, we show that Baz1a-knockout mice are viable and able to repair developmentally programmed DNA double-strand breaks in the immune system and germ line, I-SceI endonuclease-induced breaks in primary fibroblasts via homologous recombination, and DNA damage from mitomycin C exposure in vivo. However, Baz1a deficiency causes male-specific sterility in accord with its high expression in male germ cells, where it displays dynamic, stage-specific patterns of chromosomal localization. Sterility is caused by pronounced defects in sperm development, most likely a consequence of massively perturbed gene expression in spermatocytes and round spermatids in the absence of BAZ1A: the normal spermiogenic transcription program is largely intact but more than 900 other genes are mis-regulated, primarily reflecting inappropriate up-regulation. We propose that large-scale changes in chromatin composition that occur during spermatogenesis create a window of vulnerability to promiscuous transcription changes, with an essential function of ACF and/or CHRAC chromatin remodeling activities being to safeguard against these alterations.
Highlights
The nucleosome, a complex of eight histone proteins wrapped by 146 bp of DNA, is a fundamental packaging unit for nuclear DNA, controlling access by proteins involved in transcription, replication, recombination and repair
Chromatin remodeling factors are multi-protein complexes that utilize the energy released during ATP-hydrolysis to assemble, reposition, restructure and disassemble nucleosomes
We provide evidence suggesting that these large-scale alterations leave the genomic material vulnerable to spurious transcriptional changes which are normally repressed by ACF1 (BAZ1A in mammals), the defining member of the well-studied ACF/CHRAC chromatin remodeling complex
Summary
The nucleosome, a complex of eight histone proteins wrapped by 146 bp of DNA, is a fundamental packaging unit for nuclear DNA, controlling access by proteins involved in transcription, replication, recombination and repair. Granting or blocking DNA access can be effected through changes in histone-DNA contacts by action of chromatin remodelers, ATP-dependent multi-protein complexes that assemble, reposition, restructure and/or disassemble nucleosomes [1,2]. Drosophila ACF (ATP-dependent chromatin assembly and remodeling factor) is a two-subunit complex containing the ATPase ISWI bound to Acf1 [5]. Its human counterpart contains the ISWI homolog SNF2H (SMARCA5) and the Acf homolog BAZ1A ( known as ACF1) [6,7]. CHRAC (chromatin accessibility complex) is a larger version of ACF which, in addition to Acf and ISWI, contains two small histone-fold proteins: CHRAC14 and -16 in Drosophila [8,9], CHRAC15 and -17 in human [10] (Figure S1A). BAZ1A is so named because it shares domain architecture with other BAZ family members: a bromodomain adjacent to a zinc finger, typically a plant homeo domain (PHD) [11] (Figure S1B)
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