The transcription factor (TF) Ikaros zinc finger 1 (IKZF1) is essential for B-cell development, and recurrently mutated in human B-cell acute lymphoblastic leukemia (B-ALL). IKZF1 has been ascribed both activating and repressive functions via interactions with coactivator and corepressor complexes, but the relative abundance of IKZF1-associated coregulators and their contribution to IKZF1-mediated gene regulation are not well understood. To address this, we performed an unbiased identification of IKZF1-interacting proteins in pre-B cells and found that IKZF1 interacts overwhelmingly with corepressors and heterochromatin-associated proteins. Time-resolved analysis of transcription and chromatin state identified transcriptional repression as the immediate response to IKZF1 induction. Transcriptional repression preceded transcriptional activation by several hours, manifesting as a decrease in the fraction of transcriptional bursts at the single-molecule level. Repression was accompanied by a rapid loss of chromatin accessibility and reduced levels of H3K27ac, particularly at enhancers. We identified highly conserved helical motifs within the intrinsically disordered region of IKZF1 that mediate its association with the nucleosome remodeling and deacetylase (NuRD) corepressor complex through critical “KRK” residues that bind the NuRD subunit RBBP4, a mechanism shared with the TFs FOG1, BCL11A, and SALL4. Functional characterization reveals that this region is necessary for the efficient silencing of target genes and antiproliferative functions of IKZF1 in B-ALL.

中文翻译：

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IKZF1 无序区域中的保守螺旋基序介导 NuRD 相互作用和转录抑制


转录因子 （TF） Ikaros 锌指 1 （IKZF1） 对 B 细胞发育至关重要，并且在人 B 细胞急性淋巴细胞白血病 （B-ALL） 中反复突变。IKZF1 通过与共激活因子和辅阻遏物复合物的相互作用而被赋予激活和抑制功能，但 IKZF1 相关共调节因子的相对丰度及其对 IKZF1 介导的基因调控的贡献尚不清楚。为了解决这个问题，我们对前 B 细胞中 IKZF1 相互作用的蛋白进行了无偏鉴定，发现 IKZF1 与辅阻遏蛋白和异染色质相关蛋白相互作用绝大多数。转录和染色质状态的时间分辨分析确定转录抑制是对 IKZF1 诱导的直接反应。转录抑制比转录激活早数小时，表现为单分子水平转录爆发的分数减少。抑制伴随着染色质可及性的快速丧失和 H3K27ac 水平降低，尤其是在增强子处。我们在 IKZF1 的内在无序区域内鉴定了高度保守的螺旋基序，这些基序通过结合 NuRD 亚基 RBBP4 的关键“KRK”残基介导其与核小体重塑和脱乙酰酶 （NuRD） 辅阻遏蛋白复合物的结合，这种机制与 TFs FOG1 、 BCL11A 和 SALL4 共享。功能表征表明，该区域对于 B-ALL 中靶基因的有效沉默和 IKZF1 的抗增殖功能是必需的。