Division of Molecular Hematology.
Spemann Graduate School of Biology and Medicine (SGBM).
Blood. 2018 May 3;131(18):2065-2073. doi: 10.1182/blood-2017-10-810622. Epub 2018 Mar 8.
The transcription factor "nuclear factor erythroid 2" (NFE2) is overexpressed in the majority of patients with myeloproliferative neoplasms (MPNs). In murine models, elevated NFE2 levels cause an MPN phenotype with spontaneous leukemic transformation. However, both the molecular mechanisms leading to NFE2 overexpression and its downstream targets remain incompletely understood. Here, we show that the histone demethylase constitutes a novel NFE2 target gene. JMJD1C levels are significantly elevated in polycythemia vera (PV) and primary myelofibrosis patients; concomitantly, global H3K9me1 and H3K9me2 levels are significantly decreased. JMJD1C binding to the promoter is increased in PV patients, decreasing both H3K9me2 levels and binding of the repressive heterochromatin protein-1α (HP1α). Hence, JMJD1C and NFE2 participate in a novel autoregulatory loop. Depleting JMJD1C expression significantly reduced cytokine-independent growth of an MPN cell line. Independently, NFE2 is regulated through the epigenetic JAK2 pathway by phosphorylation of H3Y41. This likewise inhibits HP1α binding. Treatment with decitabine lowered H3Y41ph and augmented H3K9me2 levels at the locus in HEL cells, thereby increasing HP1α binding, which normalized NFE2 expression selectively in JAK2-positive cell lines.
转录因子“红细胞衍生的核因子 2”（NFE2）在大多数骨髓增殖性肿瘤（MPN）患者中过度表达。在鼠模型中，升高的 NFE2 水平导致自发性白血病转化的 MPN 表型。然而，导致 NFE2 过度表达的分子机制及其下游靶点仍不完全清楚。在这里，我们表明组蛋白去甲基酶 是 NFE2 的一个新的靶基因。JMJD1C 在真性红细胞增多症（PV）和原发性骨髓纤维化患者中的水平显著升高；同时，全局 H3K9me1 和 H3K9me2 水平显著降低。JMJD1C 在 PV 患者中的 启动子上的结合增加，降低了 H3K9me2 水平和抑制性异染色质蛋白-1α（HP1α）的结合。因此，JMJD1C 和 NFE2 参与了一个新的自调节回路。耗尽 JMJD1C 的表达显著降低了 MPN 细胞系的细胞因子非依赖性生长。独立地，NFE2 通过 H3Y41 的磷酸化被表观遗传 JAK2 通路调节。这同样抑制了 HP1α 的结合。地西他滨处理降低了 HEL 细胞中 H3Y41ph 的水平，并增加了 基因座处的 H3K9me2 水平，从而增加了 HP1α 的结合，这在 JAK2 阳性细胞系中选择性地上调了 NFE2 的表达。
