美国国立卫生研究院Sergio Ruiz和德国马克斯-普朗克心肺研究所Johnny Kim小组合作的最新研究发现，同源转录因子DUXBL调控细胞全能性消失。相关论文于2024年3月20日发表于国际学术期刊《自然-遗传学》杂志。

研究人员发现两细胞（2C）特异性转录因子双同源框蛋白（DUX）通过诱导DUXBL的表达来促进全能性沉默，从而介导了一个重要的负反馈循环。研究发现，DUXBL在DUX表达时可特异性进入与DUX结合的区域。

此外，研究还确定DUXBL与参与基因沉默的TRIM超家族成员TRIM24和TRIM33之间存在相互作用，并且在细胞核中DUX表达与它们共定位。重要的是，DUXBL的过表达会破坏2C相关转录，而小鼠胚胎干细胞中Duxbl的失活则会增加DUX对2C转录程序的依赖性。因此，胚胎中缺乏DUXBL会导致2C相关转录本的持续表达，从而导致早期发育停滞。该研究发现，在细胞全能性消失过程中，DUXBL是细胞命运首次分化的重要调节因子。

据了解，在小鼠中，细胞从全能的2C期胚胎中分化需要沉默2C相关的转录程序。然而，人们对这一过程的分子机制仍然知之甚少。

附：英文原文

Title: The homeobox transcription factor DUXBL controls exit from totipotency

Author: Vega-Sendino, Maria, Lttmann, Felipe F., Olbrich, Teresa, Chen, Yanpu, Kuenne, Carsten, Stein, Paula, Tillo, Desiree, Carey, Grace I., Zhong, Jiasheng, Savy, Virginia, Radonova, Lenka, Lu, Tianlin, Saykali, Bechara, Kim, Kee-Pyo, Domingo, Catherine N., Schler, Leah, Gnther, Stefan, Bentsen, Mette, Bosnakovski, Darko, Schler, Hans, Kyba, Michael, Maity, Tapan K., Jenkins, Lisa M., Looso, Mario, Williams, Carmen J., Kim, Johnny, Ruiz, Sergio

Issue&Volume: 2024-03-20

Abstract: In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in mouse embryonic stem cells increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts leading to early developmental arrest. Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates.

DOI: 10.1038/s41588-024-01692-z

Source: https://www.nature.com/articles/s41588-024-01692-z