Defective HIRA driven chromatin maintenance underlies age related decline in oocyte quality
Year: 2026
Type: preprint
Abstract: The rapid fertility decline in women over 35 years of age has been attributed to decreasing oocyte quality. Aging oocytes accumulate DNA damage, chromosome segregation defects and altered epigenetic modifications. Critically, the molecular mechanisms underlying these changes remain poorly understood. Here we uncovered that in the mouse, the HIRA driven H3.3 histone replacement is attenuated during oocyte aging leading to the loss of chromatin homeostasis. The loss of HIRA function is caused by its SUMOylation resulting in the disruption of HIRA-UBN1-CABIN1 complex and its association with chromatin. We further show that preventing HIRA SUMOylation restores H3.3 incorporation and chromatin integrity in aged mouse oocytes leading to improved oocyte maturation and preimplantation development rates. Importantly, similar chromatin homeostasis defect is observed in aging human oocytes pointing towards a conserved process. Our findings provide novel insights into the molecular mechanisms underlying age-related oocyte quality decline and pave the way for clinical interventions.
Institutions: MRC London Institute of Medical Sciences, Research Institute for Microbial Diseases, The University of Osaka, Imperial College London, Medical Research Council, The University of Osaka, Newcastle upon Tyne Hospitals NHS Foundation Trust, Centre for Life, Monash University, Newcastle University, University of Sheffield, Inner Mongolia University, New England Biolabs (United States)
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214768789