ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1.
ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1.
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DOI：
10.1182/bloodadvances.2018018309
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发表时间：
2018-09
期刊：
影响因子：
7.5
通讯作者：
N. Rohatgi;W. Zou;P. Collins;Jonathan R. Brestoff;T. H. Chen;Y. Abu-Amer;S. Teitelbaum
中科院分区：
文献类型：
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作者：
N. Rohatgi;W. Zou;P. Collins;Jonathan R. Brestoff;T. H. Chen;Y. Abu-Amer;S. Teitelbaum
额外的性梳状样1 （ASXL1）突变通常与髓系恶性肿瘤相关，是侵袭性疾病的标志。ASXL1对于髓细胞分化是必需的，这一事实提高了它也调节破骨细胞的可能性。我们发现髓系细胞中ASXL1的缺失会导致骨质流失，并增加破骨细胞的丰度。由于ASXL1是三胸和多梳（ETP）蛋白的增强子，我们想知道它是否通过维持正、负表观遗传调节因子之间的平衡来调节破骨细胞的分化。事实上，ASXL1的缺失导致抑制H3K27me3的缺失，而H3K4me3在关键破骨细胞分化基因上的增加，包括活化T细胞的核因子1 （NFATc1）和itgb3。在ASXL1缺失的情况下，增加的NFATc1与Blimp1 （Prdm1）启动子结合，从而增强该促破骨基因的表达。在asxl1缺失的破骨细胞中，K27三甲基化的整体减少也伴随着组蛋白去甲基化酶Jumonji结构域3 （Jmjd3）表达增加40倍。在asxl1缺失的破骨细胞前体中，Jmjd3敲低会增加NFATc1启动子上的H3K27me3，并损害破骨细胞的形成。因此，除了促进髓系恶性肿瘤外，ASXL1还控制破骨细胞的表观遗传重编程，以调节骨吸收和骨质量。
Additional sex comb-like 1 (ASXL1) mutations are commonly associated with myeloid malignancies and are markers of aggressive disease. The fact that ASXL1 is necessary for myeloid differentiation raises the possibility it also regulates osteoclasts. We find deletion of ASXL1 in myeloid cells results in bone loss with increased abundance of osteoclasts. Because ASXL1 is an enhancer of trithorax and polycomb (ETP) protein, we asked if it modulates osteoclast differentiation by maintaining balance between positive and negative epigenetic regulators. In fact, loss of ASXL1 induces concordant loss of inhibitory H3K27me3 with gain of H3K4me3 at key osteoclast differentiation genes, including nuclear factor for activated T cells 1 (NFATc1) and itgb3 In the setting of ASXL1 deficiency, increased NFATc1 binds to the Blimp1 (Prdm1) promoter thereby enhancing expression of this pro-osteoclastogenic gene. The global reduction of K27 trimethylation in ASXL1-deficient osteoclasts is also attended by a 40-fold increase in expression of the histone demethylase Jumonji domain-containing 3 (Jmjd3). Jmjd3 knockdown in ASXL1-deficient osteoclast precursors increases H3K27me3 on the NFATc1 promoter and impairs osteoclast formation. Thus, in addition to promoting myeloid malignancies, ASXL1 controls epigenetic reprogramming of osteoclasts to regulate bone resorption and mass.