School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, China.
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
FEBS J. 2022 Oct;289(20):6324-6341. doi: 10.1111/febs.16541. Epub 2022 Jun 19.
During Drosophila development, Polycomb-group and Trithorax group proteins function to ensure correct maintenance of transcription patterns by epigenetically repressing or activating target gene expression. To get a deep insight into the PcG and trxG pathways, we investigated a BRCT domain-containing protein called PTIP, which was generally identified as a transcriptional coactivator and belongs to the TRR complex. At the genome scale, we sorted given PTIP-binding peaks into two groups: PTIP/TRR-cobound and PTIP/PC-cobound peaks. In particular, we found that PTIP mediates the molecular switch between H3K4me3/H3K27ac and H3K27me3 histone modifications at TRR or PC occupied regions. Thus, we suggest that PTIP is a mediator rather than a dedicated co-activator along PcG and trxG pathways. Our hypothesis is further supported by the genetic assay: PTIP interacts genetically with either PcG or TrxG in a dosage-dependent manner, suggesting that PTIP functions as a co-factor of PcG/TrxG proteins. In addition, in accordance with the analysis of ChIP-seq, these genetic interactions correlate with modified ectopic HOX protein levels in imaginal discs, which reveals an essential role for PTIP in PcG-mediated Hox gene repression. Hence, we reveal a novel role for PTIP in the epigenetic regulation of gene expression along PcG and trxG pathways.
在果蝇发育过程中，多梳蛋白组和三螺旋框蛋白组通过表观遗传抑制或激活靶基因表达来确保转录模式的正确维持。为了深入了解 PcG 和 trxG 途径，我们研究了一种称为 PTIP 的 BRCT 结构域蛋白，它通常被鉴定为转录共激活因子，属于 TRR 复合物。在基因组范围内，我们将给定的 PTIP 结合峰分为两组：PTIP/TRR 共结合峰和 PTIP/PC 共结合峰。特别是，我们发现 PTIP 介导了 TRR 或 PC 占据区域的 H3K4me3/H3K27ac 和 H3K27me3 组蛋白修饰之间的分子开关。因此，我们认为 PTIP 是 PcG 和 trxG 途径中的一种介质，而不是专门的共激活因子。我们的假设得到了遗传实验的进一步支持：PTIP 以剂量依赖的方式与 PcG 或 TrxG 发生遗传相互作用，表明 PTIP 作为 PcG/TrxG 蛋白的共因子发挥作用。此外，与 ChIP-seq 的分析一致，这些遗传相互作用与 imaginal discs 中异位 HOX 蛋白水平的改变相关，这揭示了 PTIP 在 PcG 介导的 Hox 基因抑制中的重要作用。因此，我们揭示了 PTIP 在 PcG 和 trxG 途径中基因表达的表观遗传调控中的新作用。
