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Gene expression profiling of ISWI chromatin remodeler mutants before and after DNA damage

ABSTRACT: Gene expression profiling of ISWI chromatin remodeler mutants before and after DNA damage BAZ1A is a regulatory subunit within the ISWI family of chromatin remodelers in humans. We and others have shown that BAZ1A is required for efficient recovery from DNA damage. The DNA damage hypersensitivity caused by BAZ1A* is as severe as the deletion of the entire gene. This is striking given that BAZ1A* contains only two substitutions (K1181A and K1183Y) within a poorly characterized domain of BAZ1A. We find that this domain can interact with DNA, and that the mutations present in BAZ1A* hinder DNA binding. We used transcriptional profiling to identify molecular events leading to the DNA damage hypersensitivity of BAZ1A* cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95227 | GEO | 2017/07/06

SECONDARY ACCESSION(S): PRJNA376446

REPOSITORIES: GEO

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Project description:Acf1 was isolated almost 15 years ago from Drosophila embryo extracts as a subunit of several complexes that possess chromatin assembly activity. Acf1 binds to the ATPase ISWI (SNF2H in mammals) to form the ACF/CHRAC chromatin remodeling complexes. Studies in Drosophila and in human and mouse cell culture implicate Acf1 in many cellular processes including transcriptional repression, heterochromatin formation and replication, and DNA damage checkpoints and repair. However, the in vivo function of Acf1 in mammals is unknown. We generated mice deficient for Baz1a, the mammalian homolog of Drosophila Acf1. In contrast to partially penetrant lethality of the mutation in flies, Baz1a-deficient mice are viable. The mutant mice show no obvious defects in B or T cell lineages, class switch recombination in cultured B cells, or meiotic recombination. Thus, BAZ1A is dispensable in vivo for the survival and differentiation of cells that require the repair of developmentally programmed DNA double-strand breaks (DSBs). However, Baz1a-/- male mice are sterile because of a severe defect in spermiogenesis that results in fewer and non-motile sperm with morphological defects. Baz1a-deficient round spermatids display widespread perturbation of gene expression. The mutant cells faithfully execute the widespread reprogramming of gene expression that normally accompanies the developmental transition from meiosis to postmeiotic differentiation, but overlaid on this normal developmental program is mis-regulation of a large number of additional genes. The inappropriate expression of this eclectic group of genes is likely the cause of the pleiotropic spermiogenesis defects in the mutant. We propose that the dramatic changes in chromatin composition that occur in late meiotic prophase and early spermiogenesis create a window of vulnerability during which BAZ1A-targeted chromatin assembly functions are needed to prevent inappropriate transcription changes. This appears to be the sole essential function of the ACF and CHRAC complexes in mouse. total RNA isolated from FACS-enriched pachytene/diplotene spermatocytes and round spermatids from three littermate pairs of Baz1a-/- and Baz1a-/+ animals. Data from all samples are provided, but expression data for one Baz1a-/- spermatocyte sample (683_PD) was censored because of inferred high degree of contamination with round spermatids

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Gene expression profiling of ISWI chromatin remodeler mutants before and after DNA damage

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