Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Göttingen 37077, Germany.
Mol Cell. 2012 Jun 8;46(5):705-13. doi: 10.1016/j.molcel.2012.05.022.
Extensive changes in posttranslational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs) and various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction of differentiation markers and transcriptional reprogramming of hMSCs. This function is dependent upon CDK9 and the WAC adaptor protein, which are required for H2B monoubiquitination. Finally, we show that RNF40 is required for the resolution of the H3K4me3/H3K27me3 bivalent poised state on lineage-specific genes during the transition from an inactive to an active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSCs and plays a central role in controlling stem cell differentiation.
在干细胞分化过程中，转录程序的重编伴随着翻译后组蛋白修饰的广泛改变。然而，控制特定染色质修饰变化及其在分化过程中功能的机制仍知之甚少。我们发现，人骨髓间充质干细胞（hMSCs）和各种谱系定向前体细胞以及不同生物中，组蛋白 H2B 单泛素化（H2Bub1）在分化过程中显著增加。此外，H2B 泛素连接酶 RNF40 对于 hMSCs 的分化标志物诱导和转录重编程是必需的。该功能依赖于 CDK9 和 WAC 衔接蛋白，它们是 H2B 单泛素化所必需的。最后，我们发现 RNF40 对于在从无活性到活性染色质构象的转变过程中，在线粒体特异性基因上的 H3K4me3/H3K27me3 二价静止状态的分辨率是必需的。因此，这些数据表明 H2Bub1 对于维持 hMSCs 的多能性是必需的，并在控制干细胞分化中起着核心作用。
