Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease.
Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease.
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SENP1通过GATA1和MONGE病的受试者通过GATA1和BCL-XL诱导低氧诱导的多性性疾病。
DOI：
10.1084/jem.20151920
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发表时间：
2016-11-14
期刊：
影响因子：
--
通讯作者：
Haddad GG
中科院分区：
文献类型：
--
作者：
Azad P;Zhao HW;Cabrales PJ;Ronen R;Zhou D;Poulsen O;Appenzeller O;Hsiao YH;Bafna V;Haddad GG
Azad及其合作者提出，Senp 1驱动患有慢性高山病的高海拔安第斯居民的过度红细胞生成。在这项研究中，由于过度红细胞增多症是一些高海拔居民的主要特征，（慢性高山病[CMS]或蒙氏病），而不是其他生活在安第斯山脉相同海拔的人，我们利用了这个自然界的人类实验，并结合使用了诱导多能干细胞技术，基因组学，和分子生物学在这个独特的人群中，以了解缺氧诱导的过度红细胞增多症的分子基础。与海平面对照组和非CMS受试者相比，CMS细胞分别通过适度增加或根本不增加红细胞来对缺氧作出反应，CMS细胞显着增加（高达60倍）。虽然有一个开关，从胎儿到成人HgbA 0在所有人群和伴随的转变，氧结合，我们发现CMS细胞成熟更快，有更高的效率和增殖潜力比非CMS细胞。我们还确定了SENP 1在CMS和非CMS受试者的差异性红细胞生成反应中起着关键作用：我们可以通过改变SENP 1水平将CMS表型转化为非CMS表型，反之亦然。我们还证明了GATA 1是SENP 1的重要下游靶点，并且GATA 1和Bcl-xL的差异表达和反应是CMS病理学的关键机制。
Azad and collaborators propose that Senp1 drives excessive erythropoiesis in high-altitude Andean dwellers suffering from chronic mountain sickness. In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
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