Chronic Hypoxia Disrupts Spermatogenesis Through ASXL2-EZH2-Mediated Microtubule Destabilization

Area of Science:

• Reproductive Biology
• Molecular Endocrinology
• Cell Biology

Background:

• Chronic hypoxia is a known disruptor of spermatogenesis.
• The round-to-elongated spermatid transition is crucial for sperm development and is sensitive to oxygen levels.
• The additional sex combs-like 2 (ASXL2)-enhancer of zeste homolog 2 (EZH2) axis plays a regulatory role in this transition.

Purpose of the Study:

• To elucidate the molecular mechanisms by which chronic hypoxia disrupts spermatogenesis.
• To investigate the role of the ASXL2-EZH2 axis in hypoxia-induced spermatogenic failure.
• To identify potential therapeutic targets for hypoxia-related male infertility.

Main Methods:

• Analysis of ASXL2 and EZH2 expression under hypoxic conditions.
• Assessment of EZH2 binding to the CEP162 promoter.
• Measurement of H3K27me3 modification and CEP162 transcription.
• Investigation of CEP162 interaction with TUBB3 and TUBA3A.
• Evaluation of ciliary TUBB3 levels and axonemal microtubule stability.
• Correlation of molecular findings with sperm morphology and function.

Main Results:

• Hypoxia downregulates ASXL2, leading to reduced EZH2 binding to the CEP162 promoter.
• This results in decreased H3K27me3 and increased CEP162 transcription.
• Overexpressed CEP162 competes with TUBA3A for TUBB3, depleting ciliary TUBB3 and destabilizing microtubules.
• These molecular defects correlate with sperm malformations and functional deficits.
• Reduced ASXL2 and EZH2 expression is observed in infertile men.

Conclusions:

• The ASXL2-EZH2-CEP162 pathway is a critical mediator of hypoxia-induced spermatogenic disruption.
• CEP162-mediated destabilization of ciliary microtubules underlies sperm defects.
• Targeting the ASXL2-EZH2 axis presents a promising therapeutic avenue for male infertility associated with chronic hypoxia.