Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Development. 2018 Oct 11;145(19):dev166348. doi: 10.1242/dev.166348.
Suppression of Meis genes in the distal limb bud is required for proximal-distal (PD) specification of the forelimb. Polycomb group (PcG) factors play a role in downregulation of retinoic acid (RA)-related signals in the distal forelimb bud, causing Meis repression. It is, however, not known whether downregulation of RA-related signals and PcG-mediated proximal gene repression are functionally linked. Here, we reveal that PcG factors and RA-related signals antagonize each other to polarize expression along the PD axis in mouse. Supported by mathematical modeling and simulation, we propose that PcG factors are required to adjust the threshold for RA-related signaling to regulate expression. Finally, we show that a variant Polycomb repressive complex 1 (PRC1), incorporating PCGF3 and PCGF5, represses expression in the distal limb bud. Taken together, we reveal a previously unknown link between PcG proteins and downregulation of RA-related signals to mediate the phase transition of transcriptional status during forelimb patterning.
Meis 基因在远侧肢芽中的抑制对于前肢的近-远（PD）特化是必需的。多梳组（PcG）因子在下调远侧前肢芽中的视黄酸（RA）相关信号中发挥作用，导致 Meis 抑制。然而，尚不清楚 RA 相关信号的下调和 PcG 介导的近端基因抑制是否在功能上相关。在这里，我们揭示了 PcG 因子和 RA 相关信号在小鼠中沿 PD 轴相互拮抗，从而使 表达发生极化。通过数学建模和模拟的支持，我们提出 PcG 因子需要调整 RA 相关信号的阈值以调节 表达。最后，我们表明包含 PCGF3 和 PCGF5 的变体多梳抑制复合物 1（PRC1）在远侧肢芽中抑制 表达。总之，我们揭示了 PcG 蛋白与下调 RA 相关信号之间以前未知的联系，以介导前肢模式形成过程中 转录状态的相变。
