Department of Molecular & Cell Biology, University of California, Merced, CA, 95343, USA.
Department of Molecular & Cell Biology, University of California, Merced, CA, 95343, USA; Health Sciences Research Institute, University of California, Merced, CA, 95343, USA.
Dev Biol. 2024 Dec;516:196-206. doi: 10.1016/j.ydbio.2024.08.007. Epub 2024 Aug 22.
The precise regulation of transcription is required for embryonic development, adult tissue turnover, and regeneration. Epigenetic modifications play a crucial role in orchestrating and regulating the transcription of genes. These modifications are important in the transition of pluripotent stem cells and their progeny. Methylation, a key epigenetic modification, influences gene expression through changes in DNA methylation. Work in different organisms has shown that the DNA methyltransferase-1-associated protein (DMAP1) may associate with other molecules to repress transcription through DNA methylation. Thus, DMAP1 is a versatile protein implicated in a myriad of events, including pluripotency maintenance, DNA damage repair, and tumor suppression. While DMAP1 has been extensively studied in vitro, its complex regulation in the context of the adult organism remains unclear. To gain insights into the possible roles of DMAP1 at the organismal level, we used planarian flatworms that possess remarkable regenerative capabilities driven by pluripotent stem cells called neoblast. Our findings demonstrate the evolutionary conservation of DMAP1 in the planarian Schmidtea mediterranea. Functional disruption of DMAP1 through RNA interference revealed its critical role in tissue maintenance, neoblast differentiation, and regeneration in S. mediterranea. Moreover, our analysis unveiled a novel function for DMAP1 in regulating cell death in response to DNA damage and influencing the expression of axial polarity markers. Our findings provide a simplified paradigm for studying DMAP1's function in adult tissues.
转录的精确调控对于胚胎发育、成年组织更新和再生都是必需的。表观遗传修饰在协调和调控基因转录中起着关键作用。这些修饰在多能干细胞及其后代的转变中非常重要。甲基化是一种关键的表观遗传修饰，通过 DNA 甲基化的变化影响基因表达。不同生物的研究表明，DNA 甲基转移酶-1 相关蛋白 (DMAP1) 可能与其他分子结合，通过 DNA 甲基化来抑制转录。因此，DMAP1 是一种多功能蛋白，涉及多种事件，包括多能性维持、DNA 损伤修复和肿瘤抑制。虽然 DMAP1 在体外得到了广泛的研究，但它在成年生物体中的复杂调节机制仍不清楚。为了深入了解 DMAP1 在机体水平上的可能作用，我们利用具有多能干细胞（称为成体干细胞）驱动的惊人再生能力的扁形虫作为研究对象。我们的研究结果表明，DMAP1 在扁形虫 Schmidtea mediterranea 中具有进化上的保守性。通过 RNA 干扰对 DMAP1 的功能进行破坏，揭示了其在 S. mediterranea 组织维持、成体干细胞分化和再生中的关键作用。此外，我们的分析揭示了 DMAP1 在调节细胞死亡以响应 DNA 损伤和影响轴向极性标记物表达方面的新功能。我们的研究结果为研究 DMAP1 在成年组织中的功能提供了一个简化的范例。
