Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA.
Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
Hum Mol Genet. 2019 Jan 1;28(1):84-95. doi: 10.1093/hmg/ddy325.
Preterm birth (PTB) affects approximately 1 in 10 pregnancies and contributes to approximately 50% of neonatal mortality. However, despite decades of research, little is understood about the etiology of PTB, likely due to the multifactorial nature of the disease. In this study, we examined preterm and term placentas, from unassisted conceptions and those conceived using in vitro fertilization (IVF). IVF increases the risk of PTB and causes epigenetic change in the placenta and fetus; therefore, we utilized these patients as a unique population with a potential common etiology. We investigated genome-wide DNA methylation in placentas from term IVF, preterm IVF, term control (unassisted conception) and preterm control pregnancies and discovered epigenetic dysregulation of multiple genes involved in cell migration, including members of the ADAMTS family, ADAMTS12 and ADAMTS16. These genes function in extracellular matrix regulation and tumor cell invasion, processes replicated by invasive trophoblasts (extravillous trophoblasts (EVTs)) during early placentation. Though expression was similar between term and preterm placentas, we found that both genes demonstrate high expression in first- and second-trimester placenta, specifically in EVTs and syncytiotrophoblasts. When we knocked down ADAMTS12 or ADAMTS16in vitro, there was poor EVT invasion and reduced matrix metalloproteinase activity, reinforcing their critical role in placentation. In conclusion, utilizing a population at high risk for PTB, we have identified a role for ADAMTS gene methylation in regulating early placentation and susceptibility to PTB.
早产（PTB）影响大约 10%的妊娠，并导致大约 50%的新生儿死亡。然而，尽管已经进行了几十年的研究，但对于 PTB 的病因知之甚少，这可能是由于该疾病的多因素性质。在这项研究中，我们检查了未辅助受孕和体外受精（IVF）受孕的早产和足月胎盘。IVF 增加了 PTB 的风险，并导致胎盘和胎儿的表观遗传变化；因此，我们利用这些患者作为一个具有潜在共同病因的独特人群。我们研究了来自足月 IVF、早产 IVF、足月对照（未辅助受孕）和早产对照妊娠的胎盘的全基因组 DNA 甲基化，并发现了多个参与细胞迁移的基因的表观遗传失调，包括 ADAMTS 家族成员、ADAMTS12 和 ADAMTS16。这些基因在细胞外基质调节和肿瘤细胞侵袭中发挥作用，侵袭性滋养细胞（绒毛外滋养细胞（EVTs））在早期胎盘形成过程中复制了这些过程。尽管 ADAMTS12 和 ADAMTS16 在足月和早产胎盘中的表达相似，但我们发现这两个基因在第一和第二孕期胎盘均高表达，特别是在 EVTs 和合体滋养层中。当我们在体外敲低 ADAMTS12 或 ADAMTS16 时，EVT 侵袭不良且基质金属蛋白酶活性降低，这强化了它们在胎盘形成中的关键作用。总之，利用 PTB 风险较高的人群，我们确定了 ADAMTS 基因甲基化在调节早期胎盘形成和易患 PTB 中的作用。
