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Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells [Microarray transcriptomic analysis]

ABSTRACT: Although the conserved AAA ATPase – bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics and RNA-seq experiments in embryonic stem cells, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells, Atad2 becomes critical in sustaining specific gene expression programs, controlling proliferation and differentiation. Altogether, this work defines Atad2’s function as a facilitator of general chromatin-templated activities such as transcription.

ORGANISM(S): Mus musculus

PROVIDER: GSE69899 | GEO | 2016/03/24

SECONDARY ACCESSION(S): PRJNA287043

REPOSITORIES: GEO

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Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells [Microarray transcriptomic analysis]

Project description:Although the conserved AAA ATPase â bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics and RNA-seq experiments in embryonic stem cells, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells, Atad2 becomes critical in sustaining specific gene expression programs, controlling proliferation and differentiation. Altogether, this work defines Atad2âs function as a facilitator of general chromatin-templated activities such as transcription. Transcriptomic analyses comparing ES cells stably expressing anti-Atad2 shRNA versus cells expressing control shRNA, in day 3 LIF (-) differentiating ES cells (3 replicates for each condition) were performed using the Illumina MouseWG-6 v2.0 expression beadchip technology

2016-03-24 | E-GEOD-69899 | biostudies-arrayexpress

Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells [Atad2_ES_RNAseq_BI]

Project description:Although the conserved AAA ATPase – bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics and RNA-seq experiments in embryonic stem cells, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells, Atad2 becomes critical in sustaining specific gene expression programs, controlling proliferation and differentiation. Altogether, this work defines Atad2’s function as a facilitator of general chromatin-templated activities such as transcription.

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Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells [Atad2_ES_ChIPseq2_MG2]

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Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells

Project description:Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells

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The role of ATAD2 in ovarian cancer growth and progression

Project description:ATPase Family AAA domain containing 2 (ATAD2) expression is elevated in many cancer types including ovarian cancer. Therefore, we analyzed the role of ATAD2 in ovarian cancer. Pharmacological inhibition of ATAD2 expression in ovarian cancer cell lines resulted in decreased proliferation, and increased cell death.

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Functional cooperation between AAA-ATPase domain and a bromodomain.

Project description:A functional cooperation between an AAA type ATPase domain and a bromodomain has been evidenced. These two domains were identified and their activity tested in a yet uncharacterized factor, named Atad2, whose two-domain configuration remained highly conserved during evolution. In human and mouse, Atad2 is most abundantly expressed in testis and in the mouse. It has also been detected in post-meiotic stages and in mature spermatozoa. The AAA-ATPase domain was found necessary for protein multimerization and high affinity binding to acetylated nucleosomes by its bromodomain. The binding was found specific to acetylated histone H4 tail with a critical role for the acetylated K5 position. In vivo studies show that Atad2 behaves as a general repressor of transcription and possesses a chromatin “freezing” activity. Finally, we demonstrate that the induction of apoptosis leads to an early degradation of Atad2, which probably facilitates the action of apoptotic factors by increasing chromatin dynamics.

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Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells.

Project description:Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells Atad2 becomes critical in sustaining specific gene expression programmes, controlling proliferation and differentiation. Altogether, this work defines Atad2 as a facilitator of general chromatin-templated activities such as transcription.

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ATAD2 maintains the equilibrium between nucleosome assembly and disassembly

Project description:To avoid toxic histone overload, histone deposition and removal must be finely tuned. Following a series of functional studies in human, mouse and S. pombe, we show here that the AAA ATPase ATAD2 is a conserved mediator of histone removal and a regulator of histone deposition. In Atad2 knockout (KO) spermatogenic cells, the late-stage genome-wide eviction of histones and their replacement by protamines are significantly delayed. In S. pombe, deletion of abo1 leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. Identification of the corresponding suppressor mutations revealed that the causes of cell toxicity are mainly the deregulated activity of the histone chaperone HIRA and histone overload. We also show that, in Atad2 KO mouse ES cells, HIRA and FACT are trapped on nucleosomes at transcription start sites of active genes, resulting in histone overload and abnormal histone deposition on nucleosome-free regions. Overall, these data shed new light on a need for energy-consuming auxiliary factors, such as ATAD2, to maintain a balanced and dynamic histone chaperone basal activity and to avoid a deleterious histone overload.

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Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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