ATAD2 controls chromatin-bound HIRA turnover

Area of Science:

• Molecular Biology
• Genetics
• Chromatin Biology

Background:

• ATAD2 is an evolutionarily conserved protein with poorly understood functions.
• Histone chaperones like HIRA play vital roles in chromatin dynamics.
• Understanding ATAD2's role is key to deciphering gene regulation and chromatin maintenance.

Purpose of the Study:

• To investigate the conserved functions of ATAD2 across different species.
• To elucidate the functional relationship between ATAD2 and the histone chaperone HIRA.
• To understand the impact of ATAD2 on chromatin structure and gene expression.

Main Methods:

• Comparative functional studies in human, mouse, and *Schizosaccharomyces pombe*.
• Genetic analysis of ATAD2 ortholog (*abo1*) deletion and suppressor mutations in *S. pombe*.
• CRISPR/Cas9 knockout (KO) of ATAD2 in mouse embryonic stem cells and human cancer cell lines.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to map HIRA and FACT occupancy in *Atad2* KO cells.

Main Results:

• Deletion of *abo1* in *S. pombe* severely impairs cell growth, with suppressors arising from mutations interacting with HIRA.
• *ATAD2* KO in human and mouse cells leads to HIRA accumulation.
• ChIP-seq reveals that HIRA and FACT are aberrantly retained on nucleosomes at transcription start sites (TSS) in *Atad2* KO cells.
• This retention disrupts the normal nucleosome-free region at active gene TSS.

Conclusions:

• ATAD2 plays a conserved role in regulating chromatin dynamics.
• ATAD2 is essential for the proper turnover of histone chaperones like HIRA at active gene promoters.
• These findings reveal a novel regulatory mechanism involving ATAD2 in maintaining chromatin accessibility and gene expression.