Project description:Despite depression being one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments. Maladaptive transcriptional regulation within limbic neural circuits, including reward processing regions such as the nucleus accumbens (NAc), in response to chronic stress is thought to be a major contributor to the development of the syndrome. Epigenetic events?in particular, histone writers and erasers?that alter chromatin structure to regulate programs of gene expression have increasingly been associated with depression-related behavioral abnormalities in animal models and in depressed humans examined postmortem. However, very little is known about the ATP-dependent chromatin remodelers that control nucleosome positioning and the packing state of chromatin. Here we show that the ACF complex, part of the ISWI family of chromatin remodelers, is persistently and selectively upregulated in the NAc of mice that are susceptible to chronic social stress, as well as in the NAc of depressed human. We further establish that ACF induction is both necessary and sufficient for susceptibility to stress-induced depressive-like behaviors. Using ChIP-seq, we demonstrate that altered ACF binding after chronic stress is strongly correlated with altered nucleosome positioning, in particular, around the transcriptional start sites of affected genes. These alterations in ACF binding and nucleosome repositioning are associated with repressed expression of a subset of genes in animals that are susceptible to chronic stress. Together, these findings establish that active ATP-dependent chromatin remodeling by the ACF complex is a key regulator in the repression of genes that mediate susceptibility to social stress, and provide novel candidate targets for improved therapeutics of depression and other stress-related disorders. c57bl/6 mice underwent chronic social defeat stress (CSDS), and social interaction test was used to separate animals into control, susceptible and resilient groups. Nucleus accumbens (NAc) tissue was collected 48 hours after the last defeat session, and then Acf1, SNF2H ChIP-seq or H3 MNase-seq were performed based on the control, susceptible, and resilient groups. Three sequencing replicates were performed on each group.

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

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.

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CHRAC/ACF Contribute to the Repressive Ground State of Chromatin [Mnase-seq]

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