Alahari Sruthi, Post Martin, Caniggia Isabella
Lunenfeld-Tanenbaum Research Institute (S.A., I.C.), Mount Sinai Hospital, Toronto, M5T 3H7 Ontario, Canada; Department of Obstetrics and Gynecology (I.C.), University of Toronto, Toronto, M5G 1E2 Ontario, Canada; Department of Physiology (S.A., M.P., A.C.), University of Toronto, Toronto, M5S 1A8 Ontario, Canada; Department of Pediatrics (M.P.), University of Toronto, Toronto, M5G 1X8 Ontario, Canada; and The Hospital for Sick Children (M.P.), Toronto, M5G 1X8 Ontario, Canada.
Endocrinology. 2015 Aug;156(8):3012-25. doi: 10.1210/en.2015-1262. Epub 2015 Jun 2.
Persistent low oxygen is implicated in the pathogenesis of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Emerging evidence implicates a novel family of Jumonji C catalytic domain proteins as mediators of hypoxic gene expression. Here, we investigated the regulatory relationship between Jumonji C domain containing protein 6 (JMJD6) and hypoxia-inducible factor (HIF)1A in the human placenta at physiological and pathological conditions. JMJD6 expression inversely correlated with changes in oxygen tension during early placental development, ie, high at 7-9 weeks when-partial pressure of O2 is low and declining afterwards when-partial pressure of O2 increases. Moreover, JMJD6 protein was significantly elevated in early-onset preeclamptic placentae, localizing to the syncytiotrophoblast layer and syncytial knots. Exposure of primary isolated trophoblast cells, human villous explants, and JEG3 choriocarcinoma cells to low oxygen (3%) and sodium nitroprusside (inducer of oxidative stress) also resulted in elevated JMJD6 levels, which was abrogated by HIF1A knockdown. In normoxia, knockdown of JMJD6 in JEG3 cells stabilized HIF1A with a concomitant decrease in von Hippel-Lindau (VHL) tumor suppressor protein, a negative regulator of HIF1A stability. In contrast, overexpression of JMJD6 enhanced VHL expression and destabilized HIF1A. JMJD6 regulation of VHL stability did not involve the ubiquitin-proteasome system but likely occurred through lysyl hydroxylation and small ubiquitin-like modifier 1-dependent small ubiquitin-like modifierylation. In summary, our data signify a novel role for JMJD6 as an oxygen sensor in the human placenta, and alterations in the JMJD6-VHL-HIF1A feedback loop may indirectly contribute to elevated HIF1A found in preeclampsia.
持续性低氧与胎盘相关疾病（如子痫前期，一种严重的妊娠疾病）的发病机制有关。新出现的证据表明，一个新的Jumonji C催化结构域蛋白家族是缺氧基因表达的介质。在此，我们研究了含Jumonji C结构域蛋白6（JMJD6）与缺氧诱导因子（HIF）1A在生理和病理条件下于人胎盘组织中的调控关系。JMJD6的表达与胎盘早期发育过程中氧张力的变化呈负相关，即在妊娠7-9周时，氧分压较低，JMJD6表达较高，随后随着氧分压升高而下降。此外，早发型子痫前期胎盘组织中JMJD6蛋白显著升高，定位于合体滋养层和合体小结。将原代分离的滋养层细胞、人绒毛外植体和JEG3绒毛膜癌细胞暴露于低氧（3%）和硝普钠（氧化应激诱导剂）环境中也导致JMJD6水平升高，而HIF1A基因敲低可消除这种升高。在常氧条件下，JEG3细胞中JMJD6基因敲低可使HIF1A稳定，同时伴von Hippel-Lindau（VHL）肿瘤抑制蛋白减少，VHL是HIF1A稳定性的负调节因子。相反，JMJD6过表达可增强VHL表达并使HIF1A不稳定。JMJD6对VHL稳定性的调节不涉及泛素-蛋白酶体系统，可能是通过赖氨酰羟化和小泛素样修饰物1依赖性小泛素样修饰作用实现的。总之，我们的数据表明JMJD6在人胎盘中作为氧传感器具有新的作用，JMJD6-VHL-HIF1A反馈回路的改变可能间接导致子痫前期中HIF1A升高。
