Cross‐talk between Histone Modifications Modulate Chromatin Reader Activity of the ATAD2B Bromodomain

Abstract

The ATPase family, AAA domain‐containing protein 2 (ATAD2, or ANCCA) is an AAA nuclear co‐regulator protein containing two ATPase domains and a bromodomain. It’s closely related paralogue, ATAD2B (KIAA1240), also contains two ATPase domains and a bromodomain. The AAA ATPase domains are broadly associated with ATP driven molecular remodeling reactions while the bromodomains are evolutionarily conserved, chromatin ‘reader’ domains, known to regulate gene expression through recognition of histone post‐translational modifications (PTMs).Extensive studies on ATAD2 discuss its upregulation and correlation with poor prognosis in various cancers specially breast cancer and have successfully mapped the different histone interactions needed for targeting ATAD2 to the chromatin. Despite sharing high structural and sequence similarity with ATAD2, little is known about the unique role of ATAD2B. ATAD2B is expressed during neuronal differentiation and in tumor progression. However, limited information is available on how ATAD2B is involved or upregulated in various tumors specially in breast cancer. Our group has recently published a broad range of histone modifications recognized by the ATAD2B bromodomain. These modifications mostly include acetyllysine moieties on histone H4.Here, we present a more detailed structural and functional insight into how various histone post‐translational cross‐talk can modulate the chromatin ‘reader’ activity of ATAD2B bromodomain. Through ITC, solution NMR spectroscopy and X‐ray crystallography we demonstrate how combinations of PTMs can influence and regulate histone recognition by ATAD2B bromodomain. The studies also involve histone variants associated with breast cancer. These in‐vitro studies followed by in‐vivo analysis in breast cancer cells (MCF7) will further characterize the physiologically relevant, histone PTMs that are recognized by ATAD2B to direct it to the chromatin, thus playing a crucial role in activation of gene transcription.Through our study we highlight the importance of cross‐talk between various histone post‐translational modifications and how they may regulate the ATAD2B bromodomain activity. These combinations of PTMs can either promote or inhibit the affinity of ATAD2B to the chromatin and in turn regulate gene transcription. Understanding the molecular mechanisms driving these interactions will provide new insights for the development of therapeutic interventions for the treatment of various diseases.