Ikaros antagonizes DNA binding by STAT5 in pre-B cells.
Ikaros antagonizes DNA binding by STAT5 in pre-B cells.
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DOI：
10.1371/journal.pone.0242211
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Kastner P
中科院分区：
文献类型：
--
作者：
Heizmann B;Le Gras S;Simand C;Marchal P;Chan S;Kastner P
IKZF1基因编码Ikaros转录因子，在表达致癌基因（如BCR-ABL）的b细胞前体急性淋巴细胞白血病患者中，IKZF1基因经常被删除或突变，BCR-ABL可激活JAK-STAT5通路。Ikaros在B细胞发育过程中可拮抗IL-7/STAT5下游转录程序，以及白血病细胞中STAT5的活性。然而，Ikaros干扰STAT5功能的机制尚不清楚。我们研究了Ikaros和STAT5在小鼠b前细胞系染色质上的基因组分布，发现这两种蛋白在大约60%的STAT5靶区共定位。引人注目的是，在Ikaros诱导的两小时内，Ikaros活性导致STAT5在大多数基因组靶点的结合广泛丧失，这表明了一个直接的机制。Ikaros没有改变总STAT5蛋白或磷酸化STAT5蛋白的水平，也没有与STAT5相关。利用Ikaros和STAT5靶向的Cish、Socs2和Bcl6基因序列，我们发现这两种蛋白在GGAA基序上结合重叠序列。我们的研究结果表明，Ikaros拮抗STAT5 DNA结合，部分原因是通过竞争共同的靶序列。我们的研究有助于理解Ikaros和STAT5在B细胞发育和转化中的功能。
The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation.
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影响因子：
30.5
作者：
Katerndahl CDS;Heltemes-Harris LM;Willette MJL;Henzler CM;Frietze S;Yang R;Schjerven H;Silverstein KAT;Ramsey LB;Hubbard G;Wells AD;Kuiper RP;Scheijen B;van Leeuwen FN;Müschen M;Kornblau SM;Farrar MA
通讯作者：
Farrar MA
影响因子：
--
作者：
Langmead, Ben
通讯作者：
Langmead, Ben
影响因子：
30.5
作者：
Schwickert TA;Tagoh H;Gültekin S;Dakic A;Axelsson E;Minnich M;Ebert A;Werner B;Roth M;Cimmino L;Dickins RA;Zuber J;Jaritz M;Busslinger M
通讯作者：
Busslinger M
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
16.6
作者：
McDonald PW;Read KA;Baker CE;Anderson AE;Powell MD;Ballesteros-Tato A;Oestreich KJ
通讯作者：
Oestreich KJ