Department of Biology, Brandeis University, Waltham, MA, 02453, USA.
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA.
Nat Commun. 2024 Jul 25;15(1):6276. doi: 10.1038/s41467-024-50538-z.
HP1 proteins are essential for establishing and maintaining transcriptionally silent heterochromatin. They dimerize, forming a binding interface to recruit diverse chromatin-associated factors. Although HP1 proteins are known to rapidly evolve, the extent of variation required to achieve functional specialization is unknown. To investigate how changes in amino acid sequence impacts heterochromatin formation, we performed a targeted mutagenesis screen of the S. pombe HP1 homolog, Swi6. Substitutions within an auxiliary surface adjacent to the HP1 dimerization interface produce Swi6 variants with divergent maintenance properties. Remarkably, substitutions at a single amino acid position lead to the persistent gain or loss of epigenetic inheritance. These substitutions increase Swi6 chromatin occupancy in vivo and altered Swi6-protein interactions that reprogram H3K9me maintenance. We show how relatively minor changes in Swi6 amino acid composition in an auxiliary surface can lead to profound changes in epigenetic inheritance providing a redundant mechanism to evolve HP1-effector specificity.
HP1 蛋白对于建立和维持转录沉默的异染色质是必不可少的。它们二聚化，形成一个结合界面，招募各种与染色质相关的因子。虽然已知 HP1 蛋白能够快速进化，但实现功能特化所需的变异程度尚不清楚。为了研究氨基酸序列的变化如何影响异染色质的形成，我们对 S. pombe 的 HP1 同源物 Swi6 进行了靶向诱变筛选。与 HP1 二聚化界面相邻的辅助表面内的取代会产生具有不同维持特性的 Swi6 变体。值得注意的是，单个氨基酸位置的取代会导致表观遗传遗传的持续获得或丧失。这些取代增加了体内 Swi6 染色质的占有率，并改变了 Swi6-蛋白相互作用，从而重新编程了 H3K9me 的维持。我们展示了相对较小的 Swi6 氨基酸组成变化如何在辅助表面中导致表观遗传遗传的深刻变化，提供了一种冗余的机制来进化 HP1-效应物特异性。
