LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease.
LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease.
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DOI：
10.1038/ncb2135
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发表时间：
2011-01
影响因子：
21.3
通讯作者：
Göttgens B
中科院分区：
文献类型：
--
作者：
Griffiths DS;Li J;Dawson MA;Trotter MW;Cheng YH;Smith AM;Mansfield W;Liu P;Kouzarides T;Nichols J;Bannister AJ;Green AR;Göttgens B
酪氨酸激酶JAK2的激活突变会导致骨髓增生性肿瘤，这是一种有白血病转化倾向的克隆性血液干细胞疾病。通过JAK-STAT的LIF信号使ES细胞能够自我更新。在这里，我们证明了携带人类JAK2V617F突变的小鼠ES细胞可以在没有细胞因子或小分子抑制剂的情况下在化学定义的条件下自我更新，而不是通过STAT3或PI3K通路的JAK信号。最近发现JAK2对组蛋白H3Y41的磷酸化干扰了Hp1的α结合。染色质结合的Hp1α在JAK2V617F ES细胞中较低，但在JAK2抑制后增加，与H3Y41ph的整体降低相一致。抑制JAK2使NANOG减少，H3Y41ph降低，同时在NANOG启动子处Hp1α增加。此外，JAK2V617F ES细胞的因子非依赖性需要Nanog。综上所述，这些结果揭示了JAK2作为ES细胞自我更新的重要媒介直接向染色质发送信号的先前未被认识的作用。
Activating mutations in the tyrosine kinase JAK2 cause myeloproliferative neoplasms, clonal blood stem cell disorders with a propensity for leukaemic transformation. LIF signalling through JAK-STAT enables ES cell self-renewal. Here we show that mouse ES cells carrying the human JAK2V617F mutation could self-renew in chemically defined conditions without cytokines or small molecule inhibitors independently of JAK signalling through STAT3 or PI3K pathways. Phosphorylation of histone H3Y41 by JAK2 was recently shown to interfere with HP1α binding. Chromatin bound HP1α was lower in JAK2V617F ES cells but increased following JAK2 inhibition, coincident with a global reduction in H3Y41ph. JAK2 inhibition reduced Nanog, with a reduction in H3Y41ph and concomitant increase in HP1α at the Nanog promoter. Furthermore, Nanog was required for factor-independence of JAK2V617F ES cells. Taken together, these results uncover a previously unrecognised role for direct signalling to chromatin by JAK2 as an important mediator of ES cell self-renewal.
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