ATXN3 controls DNA replication and transcription by regulating chromatin structure

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Ataxin-3 (ATXN3) is a deubiquitinating enzyme with a polyglutamine (PolyQ) tract.
• Expanded PolyQ in ATXN3 causes spinocerebellar ataxia type-3 (SCA3).
• ATXN3 has known roles in transcription and DNA repair.

Purpose of the Study:

• To investigate the role of ATXN3 in chromatin organization under normal conditions.
• To elucidate the catalytic-independent functions of ATXN3.
• To understand the relationship between ATXN3, HDAC3, and disease pathology.

Main Methods:

• Analysis of nuclear and nucleolar morphology in ATXN3-deficient cells.
• Assessment of DNA replication timing and transcription levels.
• Evaluation of chromatin accessibility using histone H1 mobility, epigenetic marks, and nuclease sensitivity.
• Investigating the interaction and localization of ATXN3 and HDAC3.

Main Results:

• ATXN3 deficiency causes nuclear/nucleolar abnormalities, altered replication timing, and increased transcription.
• Lack of ATXN3 leads to more open chromatin, evidenced by increased histone H1 mobility and altered epigenetic marks.
• ATXN3 absence is epistatic to HDAC3 inhibition/lack, decreasing HDAC3 chromatin recruitment and altering its subcellular distribution.
• PolyQ-expanded ATXN3 mimics null mutant effects on replication, epigenetics, and HDAC3 localization.

Conclusions:

• ATXN3 plays a crucial, catalytic-independent role in maintaining chromatin organization.
• ATXN3 regulates the subcellular localization and chromatin association of HDAC3.
• Polyglutamine expansion in ATXN3 disrupts these functions, providing insights into SCA3 pathogenesis.