The Eleven-Nineteen Lysine-rich Leukemia Gene (ELL2) Influences the Histone H3 Protein Modifications Accompanying the Shift to Secretory Immunoglobulin Heavy Chain mRNA Production
The Eleven-Nineteen Lysine-rich Leukemia Gene (ELL2) Influences the Histone H3 Protein Modifications Accompanying the Shift to Secretory Immunoglobulin Heavy Chain mRNA Production
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DOI：
10.1074/jbc.m111.272096
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发表时间：
2011-09-30
影响因子：
4.8
通讯作者：
Park, Kyung Soo
中科院分区：
文献类型：
--
作者：
Milcarek, Christine;Albring, Michael;Park, Kyung Soo
在浆细胞中，免疫球蛋白重链（IgH）分泌特异性mRNA的高丰度是启动子近端多聚(a)位点选择增加和弱剪接位点跳变的结果。Ell2，富含1119赖氨酸的白血病基因，是一种转录延伸因子，在浆细胞中被诱导6倍，并已被证明可以驱动分泌特异性mRNA的产生。通过siRNA减少ELL2，减少了分泌特异性poly(A)位点的加工，也影响了IgH基因上组蛋白H3K4和H3K79的甲基化，并影响了阳性转录因子b （pTEFb）、Ser-2羧基末端磷酸化和RNA聚合酶II的聚腺苷化因子添加。在缺乏ELL2的情况下，多谱系白血病基因（MLL）和与IgH基因相关的Dot1L也受到损害。为了研究组蛋白修饰、转录延伸和替代RNA加工在IgH mRNA产生中的联系，我们对培养的携带相同IgH γ 2a基因的小鼠B细胞和浆细胞进行了染色质免疫沉淀。在浆细胞中，与B细胞相比，H3K4和H3K79甲基化延伸到更远的下游，经过IgH增强子到达转录区域的末端。因此，浆细胞中IgH相关染色质的下游H3K4和H3K79甲基化与ELL2转录延伸因子的作用导致的聚腺苷化和外显子跳变增加有关。
In plasma cells, immunoglobulin heavy chain (IgH) secretory-specific mRNA is made in high abundance as a result of both increased promoter proximal poly(A) site choice and weak splice-site skipping. Ell2, the eleven-nineteen lysine rich leukemia gene, is a transcription elongation factor that is induced similar to 6-fold in plasma cells and has been shown to drive secretory-specific mRNA production. Reducing ELL2 by siRNA, which reduced processing to the secretion-specific poly(A) site, also influenced the methylations of histone H3K4 and H3K79 on the IgH gene and impacted positive transcription factor b (pTEFb), Ser-2 carboxyl-terminal phosphorylation, and polyadenylation factor additions to RNA polymerase II. The multiple lineage leukemia gene (MLL) and Dot1L associations with the IgH gene were also impaired in the absence of ELL2. To investigate the link between histone modifications, transcription elongation, and alternative RNA processing in IgH mRNA production, we performed chromatin immunoprecipitation on cultured mouse B and plasma cells bearing the identical IgH gamma 2a gene. In the plasma cells, as compared with the B cells, the H3K4 and H3K79 methylations extended farther downstream, past the IgH enhancer to the end of the transcribed region. Thus the downstream H3K4 and H3K79 methylation of the IgH associated chromatin in plasma cells is associated with increased polyadenylation and exon skipping, resulting from the actions of ELL2 transcription elongation factor.