Defective HIRA driven chromatin maintenance underlies age related decline in oocyte quality

Hatanaka, Y., Takeda, Y., Hannam, M., Cutts, E. E., Nashun, B., Dore, M., Moyon, B., Young, G., Esteve, P.-O., Pradhan, S. E., Herbert, M., Hajkova, P.

MRC Laboratory of Medical Sciences (MRC LMS), Du Cane Rd, W12 0HS London, UKMRC Laboratory of Medical Sciences (MRC LMS), Du Cane Rd, W12 0HS London, UK · biorxiv

Paper

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.

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Research summary

Preventing HIRA SUMOylation restores H3.3 incorporation and chromatin integrity in aged oocytes, improving maturation and development rates. This paper is relevant because it identifies a specific molecular mechanism (epigenetic chromatin maintenance failure) underlying a fundamental aspect of biological aging (reproductive senescence) and demonstrates that intervening on this root cause can reverse the functional decline, rather than merely treating downstream symptoms.

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