Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia.
Department of Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, Virginia.
J Cell Biochem. 2018 Jun;119(6):4644-4655. doi: 10.1002/jcb.26636. Epub 2018 Mar 9.
Myt1 and Myt1l (Myelin transcription factor 1, and Myt1-like) are members of a small family of closely related zinc finger transcription factors, characterized by two clusters of C2HC zinc fingers. Both are widely expressed during early embryogenesis, but are largely restricted to expression within the brain in the adult. Myt1l, as part of a three transcription factor mix, can reprogram fibroblasts to neurons and plays a role in maintaining neuronal identity. Previous analyses have indicated roles in both transcriptional activation and repression and suggested that Myt1 and Myt1l may have opposing functions in gene expression. We show that when targeted to DNA via multiple copies of the consensus Myt1/Myt1l binding site Myt1 represses transcription, whereas Myt1l activates. By targeting via a heterologous DNA binding domain we mapped an activation function in Myt1l to an amino-terminal region that is poorly conserved in Myt1. However, genome wide analyses of the effects of Myt1 and Myt1l expression in a glioblastoma cell line suggest that the two proteins have largely similar effects on endogenous gene expression. Transcriptional repression is likely mediated by binding to DNA via the known consensus site, whereas this site is not associated with the transcriptional start sites of genes with higher expression in the presence of Myt1 or Myt1l. This work suggests that these two proteins function similarly, despite differences observed in analyses based on synthetic reporter constructs.
Myt1 和 Myt1l（髓鞘转录因子 1 和 Myt1 样）是一小族紧密相关的锌指转录因子的成员，其特征是两个 C2HC 锌指簇。两者在早期胚胎发生过程中广泛表达，但在成年期主要局限于大脑内表达。Myt1l 作为三个转录因子混合物的一部分，可以将成纤维细胞重编程为神经元，并在维持神经元身份方面发挥作用。先前的分析表明它们在转录激活和抑制中都有作用，并表明 Myt1 和 Myt1l 可能在基因表达中具有相反的功能。我们表明，当通过多个共识 Myt1/Myt1l 结合位点靶向 DNA 时，Myt1 抑制转录，而 Myt1l 则激活转录。通过靶向异源 DNA 结合域，我们将 Myt1l 的激活功能映射到在 Myt1 中保守性较差的氨基末端区域。然而，在神经胶质瘤细胞系中对 Myt1 和 Myt1l 表达的全基因组分析表明，这两种蛋白质对内源性基因表达的影响大致相似。转录抑制可能是通过已知的共识结合位点与 DNA 结合介导的，而该位点与在存在 Myt1 或 Myt1l 时表达较高的基因的转录起始位点无关。这项工作表明，尽管在基于合成报告基因构建体的分析中观察到差异，但这两种蛋白质的功能相似。
