Cabrita Brigite, Enyioko Mary, Martinho Rui Gonçalo
Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Agra do Crasto, Edifício 30, 3810-193 Aveiro, Portugal.
J Dev Biol. 2025 Aug 19;13(3):30. doi: 10.3390/jdb13030030.
Female gametogenesis is orchestrated by dynamic epigenetic modifications. In mammals, SETDB1, a histone H3K9 methyltransferase, is required for proper meiotic progression and early embryonic development. In , the ortholog of SETDB1 plays a critical role in germ cell differentiation, transposon silencing, and the transcriptional repression of specific germline genes during oocyte fate determination. Moreover, Polycomb group (PcG) proteins in both mammals and are essential for primary oocyte viability and meiosis, functioning through the silencing of early prophase I genes during later stages of prophase. While the repressive roles of epigenetic regulators in both and mammalian oogenesis are well characterized, the functions of epigenetic activators remain less defined. Gene expression is controlled by the opposing activities of PcG and Trithorax group (TrxG) proteins, with the latter constituting a diverse family of chromatin remodelling factors that include H3K4 methyltransferases. In , SET domain containing 1 (Set1)-the ortholog of mammalian SETD1A/B-acts as the primary regulator of global H3K4me2/3 levels. Set1 is critical for germline stem cell (GSC) self-renewal, functioning through both cell-autonomous and non-cell-autonomous mechanisms, with its depletion in the germline resulting in a progressive loss of GSC. More recently, Set1 has been implicated in germline cyst differentiation, although the mechanisms underlying this role remain poorly understood due to the complexity of the observed phenotypes. To investigate this, we analyzed ovaries from recently eclosed females in which Set1 and its highly conserved COMPASS partner, absent, small, or homeotic discs 2 (Ash2), were depleted-thus minimizing the confounding effects from GSC loss. We observed striking defects in both oocyte determination and Synaptonemal Complex (SC) integrity in one- to two-day-old females, within otherwise normal egg chambers. Interestingly, while defects in oocyte fate and oocyte-chromatin architecture were partially recovered in older egg chambers, SC integrity remained compromised. These findings suggest a critical window for SC assembly during germline cyst differentiation, after which this assembly cannot occur.
雌性配子发生由动态表观遗传修饰精心调控。在哺乳动物中，组蛋白H3K9甲基转移酶SETDB1是减数分裂正常进行和早期胚胎发育所必需的。在[具体物种名称未给出]中，SETDB1的直系同源物在生殖细胞分化、转座子沉默以及卵母细胞命运决定过程中特定生殖系基因的转录抑制中起关键作用。此外，哺乳动物和[具体物种名称未给出]中的多梳蛋白家族（PcG）蛋白对于初级卵母细胞的存活和减数分裂至关重要，它们通过在减数分裂前期后期沉默前期I早期基因发挥作用。虽然表观遗传调节因子在[具体物种名称未给出]和哺乳动物卵子发生中的抑制作用已得到充分表征，但表观遗传激活因子的功能仍不太明确。基因表达受PcG和三胸蛋白家族（TrxG）蛋白相反活性的控制，后者构成了一个多样化的染色质重塑因子家族，包括H3K4甲基转移酶。在[具体物种名称未给出]中，含SET结构域1（Set1）——哺乳动物SETD1A/B的直系同源物——作为全局H3K4me2/3水平的主要调节因子。Set1对生殖系干细胞（GSC）的自我更新至关重要，通过细胞自主和非细胞自主机制发挥作用，其在生殖系中的缺失会导致GSC逐渐丧失。最近，Set1与生殖系囊肿分化有关，尽管由于观察到的表型复杂，其作用机制仍知之甚少。为了研究这一点，我们分析了刚羽化雌性的卵巢，其中Set1及其高度保守的COMPASS伴侣、缺失、小或同源异型盘2（Ash2）被耗尽，从而最大限度地减少了GSC损失带来的混杂效应。我们在一到两天大的雌性中观察到，在原本正常的卵室中，卵母细胞决定和联会复合体（SC）完整性都存在明显缺陷。有趣的是，虽然卵母细胞命运和卵母细胞染色质结构缺陷在较老的卵室中部分得到恢复，但SC完整性仍然受损。这些发现表明在生殖系囊肿分化过程中存在一个SC组装的关键窗口，在此之后这种组装无法发生。
