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

Abstract

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.

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

“…A recent study showed that ATAD2 is highly expressed in replicating PC cells and ATAD2 expression correlates with expression of cell cycle and DNA replication genes that have overlapping function in meiosis and tumor progression (Koo et al, 2016). Moreover, in highly proliferating embryonic stem cells, ATAD2 was reported to sustain specific gene expression programs via regulating chromatin opening guided by histone acetylation (Morozumi et al, 2016), which is in agreement with our data. These findings corroborate our data and are supportive of ATAD2 being a possible contributor to increased transcription plasticity in CRPC.…”

Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain

“…15 One such bromodomain-containing protein is the ATPase family, AAA domain-containing protein 2 (ATAD2, UniProtKB Q6PL18, also called ANCCA/PRO 2000). 16 ATAD2 has been shown to recognize histone H4 that is acetylated at lysine 5 (H4K5ac) and lysine 12 (H4K12ac), 17,18 and has recently been proposed to function as a reader of newly synthesized H4K5acK12ac di-acetyllysine marks during DNA replication. 19 Several studies suggest a role for ATAD2 in the pathogenesis of cancer where it functions as a co-regulator of oncogenic transcription factors including E2F, 20,21 the estrogen receptorα, 16 the androgen receptor 22 , and MYC.…”

A Chemical Probe for the ATAD2 Bromodomain

“…Therefore,w ec annot be sure that the effects were caused by ATAD2 inhibition, although they were not seen to such an extent with the negative control 17.C onsidering the in vitro potencya nd permeability of 16,these results suggest that the opportunity to regulate proliferation in atherapeutic context via the ATAD2 bromodomain may be limited. [22] Hence,w eh ope that reporting this probe,G SK8814 (16)and its less active control GSK8815 (17), to the scientific community will enable others to investigate the biology of ATAD2 further. [18,19] Another group recently concluded that the ATPases of the SMARCA2/4 proteins provide better oncology opportunities than their bromodomains.…”

“…Fori nstance,i th as recently been proposed that ATAD2 has am ore critical function in differentiating embryonic stem cells. [22] Hence,w eh ope that reporting this probe,G SK8814 (16)and its less active control GSK8815 (17), to the scientific community will enable others to investigate the biology of ATAD2 further. We recommend not exceeding low-micromolar compound concentrations in cells to avoid any possible unknown off-target effects.…”