rs3734637 — HEY2

HEY2 — A Notch Transcription Factor at the Foundation of the Follicle Reserve

Every egg a woman will ever ovulate was set aside before she was born. Between embryonic day 13 and the first weeks of postnatal life, primordial oocytes cluster in [germ cell nests | syncytial cysts where 10–30 oocytes share cytoplasm through intracellular bridges, formed during the proliferative phase of oogonial division] that must be broken apart and individually wrapped in flattened granulosa cells to form the primordial follicles that constitute the ovarian reserve. The efficiency of this assembly process — how many oocytes survive, and how many are culled by apoptosis during nest breakdown — determines the starting size of the follicle pool that a woman draws down across her reproductive lifespan.

HEY2¹¹ HEY2
Hairy/Enhancer-of-split Related with YRPW Motif protein 2; a bHLH transcriptional repressor that serves as a downstream effector of the Notch signaling pathway in developing follicles is one of the key molecules controlling this critical window. rs3734637 is a variant in HEY2's 3'UTR — the regulatory tail end of the mRNA — where it can influence mRNA stability, polyadenylation site selection, or microRNA binding.

The Mechanism

During the neonatal period when follicle assembly occurs, the Notch2 receptor is activated in pregranulosa cells by the Jagged1 ligand expressed on adjacent oocytes. This Notch2 signal drives transcription of HES1 and HEY2²² HES1 and HEY2
two related bHLH repressor proteins; their shared YRPW motif mediates interaction with the NuRD histone deacetylase complex, compacting chromatin at target gene loci to silence them. The downstream effect of this HEY2 activation in pregranulosa cells is non-cell-autonomous control of oocyte apoptosis — precisely calibrating how many oocytes survive nest breakdown versus how many are sacrificed to provide materials for the survivors.

HEY2 exerts its repressive function in part through physical association with SIRT1³³ SIRT1
an NAD+-dependent class III histone deacetylase; the same enzyme activated by NMN/NR supplementation that supports DNA repair in oocytes. Iso et al. 2003 demonstrated that SIRT1 co-immunoprecipitates with HEY2 and participates in its transcriptional repression at Notch target loci — connecting the HEY2-Notch axis to the broader chromatin state circuitry that also governs oocyte DNA integrity.

The G allele at rs3734637 is the GRCh38 reference and represents the baseline HEY2 regulatory state. The T allele is the derived alternate allele, present at approximately 55% globally (rising to ~75% in East Asian populations), and may mark elevated HEY2 mRNA stability or translation efficiency — effectively providing a modest boost to the Notch-HEY2 signal during follicle assembly. This pattern parallels rs9796 in the INO80 3'UTR, where the non-reference T allele is similarly associated with higher expression and better ovarian reserve.

The Evidence

The most direct functional evidence comes from two independent lines:

Trombly et al. 2008⁴⁴ Trombly et al. 2008
Suppression of Notch signaling in the neonatal mouse ovary decreases primordial follicle formation. Endocrinology 150:1014–1024 used gamma-secretase inhibitors to block Notch signaling in neonatal mouse ovaries and measured follicle assembly outcome. Inhibitor-treated ovaries retained 64% of germ cells in nests versus 42% in controls, while primordial follicle formation fell from 58% to 35% — a 40% reduction. Critically, Hey2 mRNA increased 5-fold between postnatal days 0 and 6 in controls, and HEY2 transcript was localized specifically to pregranulosa cells of primordial follicles. Blocking Notch prevented this Hey2 upregulation and impaired follicle assembly.

Xu & Gridley 2013⁵⁵ Xu & Gridley 2013
Notch2 is required in somatic cells for breakdown of ovarian germ-cell nests and formation of primordial follicles. BMC Biology 11:13 established the causal pathway in vivo: female mice with somatic-cell-specific Notch2 deletion showed impaired germ-cell nest breakdown, multi-oocyte follicle formation, and reduced fertility. The mechanism is non-cell-autonomous — HEY2 in pregranulosa cells signals back to regulate oocyte apoptosis, providing a precise mechanism by which variation in HEY2 expression levels could alter the size of the primordial follicle pool established at birth.

The HEY2-SIRT1 physical association (Iso et al. 2003, Biochem Biophys Res Commun 301:250–257, PMID 12535671) places this variant at the intersection of the Notch-follicle-formation axis and the broader NAD+/chromatin remodeling network that governs ovarian aging.

The rs3734637 G allele reached genome-wide significance (p=3×10⁻⁸) for height in the Yengo et al. 2022 GIANT GWAS⁶⁶ Yengo et al. 2022 GIANT GWAS
Ultra-large GWAS of 5+ million individuals; the largest human height study to date, confirming this as a functional regulatory variant in HEY2's 3'UTR with measurable effects on gene expression — though the reproductive biology connection has not yet been tested in a dedicated human GWAS of ovarian reserve or age at natural menopause.

Practical Actions

Since the reproductive biology evidence is from mouse models and the confirmed human GWAS association is to height rather than fertility, actions for GG carriers are monitoring-focused. Follicle pool size is determined before birth, so the relevant biological window cannot be intervened on directly. What can be done is tracking the reserve from a younger baseline to detect any accelerated decline early, and maintaining the NAD+/SIRT1 axis that HEY2 depends on.

Interactions

HEY2 operates downstream of the Notch2-Jagged1 signaling cascade that governs granulosa-oocyte communication during follicle assembly. The most relevant interaction partner in the GeneOps database is rs9796 (INO80) — INO80's role in DNA double-strand break repair during meiotic recombination in oocytes and HEY2's role in controlling the size of the primordial follicle pool represent convergent mechanisms shaping ovarian reserve. Carriers of GG at rs3734637 (baseline HEY2 signaling, no T allele boost) alongside AA at rs9796 (baseline INO80 repair activity) could face compounding disadvantage: a potentially smaller starting follicle pool combined with less efficient repair of the DNA damage that depletes it over time.

rs2277339 (PRIM1) is a second relevant partner: PRIM1 DNA primase efficiency and HEY2 follicle-assembly signaling represent independent pathways both contributing to functional ovarian reserve. Women lacking protective alleles at both loci may have a broader polygenic disadvantage that warrants earlier and more proactive ovarian reserve monitoring.