Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis
Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis
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TAL1癌蛋白和LSD1之间的动态相互作用调节TAL1在造血和白血病发生中的功能
DOI：
10.1038/onc.2012.8
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发表时间：
2012-11-01
期刊：
影响因子：
8
通讯作者：
Huang, S.
中科院分区：
文献类型：
--
作者：
Li, Y.;Deng, C.;Huang, S.
TAL 1/SCL是一种造血特异性癌基因，其活性受相关转录辅激活子和辅抑制子的调控。TAL 1活性失调与T细胞白血病发生有关。然而，目前还不清楚TAL 1和辅抑制因子与辅激活因子之间的相互作用是如何被适当调节的。在这里，我们报道了蛋白激酶A（PKA）介导的磷酸化调节TAL 1与赖氨酸特异性脱甲基酶（LSD 1）的相互作用，LSD 1从组蛋白H3尾部的甲基化赖氨酸4中去除甲基。TAL 1中丝氨酸172的磷酸化特异性地使TAL 1-LSD 1相互作用不稳定，导致启动子H3 K4超甲基化和靶基因的激活，这些靶基因在正常和恶性造血中被抑制。TAL 1或LSD 1的敲低导致T细胞急性淋巴母细胞白血病（T-ALL）Jurkat细胞中TAL 1靶基因的去抑制，这伴随着启动子H3 K4甲基化的升高。类似地，PKA激活剂forskolin的治疗通过减少其与LSD 1的相互作用而导致靶基因的去抑制，而PKA抑制剂H89通过抑制H3 K4甲基化水平而抑制靶基因。与TAL 1在转录中的双重作用一致，在红系分化期间，TAL 1相关的LSD 1减少，而在TAL 1靶点处hSET 1的募集增加。这一过程伴随着H3 K4甲基化的急剧增加。因此，我们的数据揭示了PKA磷酸化和TAL 1介导的表观遗传调节之间的新的相互作用，调节造血和白血病发生过程中的造血转录和分化程序。
TAL1/SCL is a hematopoietic-specific oncogene and its activity is regulated by associated transcriptional co-activators and corepressors. Dysregulation of TAL1 activity has been associated with T-cell leukemogenesis. However, it remains unclear how the interactions between TAL1 and corepressors versus co-activators are properly regulated. Here, we reported that protein kinase A (PKA)-mediated phosphorylation regulates TAL1 interaction with the lysine-specific demethylase (LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails. Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1–LSD1 interaction leading to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis. Knockdown of TAL1 or LSD1 led to a derepression of the TAL1 target genes in T-cell acute lymphoblast leukemia (T-ALL) Jurkat cells, which is accompanied by elevating promoter H3K4 methylation. Similarly, treatment of PKA activator forskolin resulted in derepression of target genes by reducing its interaction with LSD1 while PKA inhibitor H89 represses them by suppressing H3K4 methylation levels. Consistent with the dual roles of TAL1 in transcription, TAL1-associated LSD1 is decreased while recruitment of hSET1 is increased at the TAL1 targets during erythroid differentiation. This process is accompanied by a dramatic increase in H3K4 methylation. Thus, our data revealed a novel interplay between PKA phosphorylation and TAL1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis.