Ching Reagan W, Świst-Rosowska Kalina M, Erikson Galina, Koschorz Birgit, Engist Bettina, Jenuwein Thomas
Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Freiburg, Germany.
Nat Commun. 2025 Jul 11;16(1):6420. doi: 10.1038/s41467-025-61586-4.
Mouse heterochromatin is characterised by transcriptionally competent major satellite repeat (MSR) sequences and it has been proposed that MSR RNA contributes to the integrity of heterochromatin. We establish an inducible dCas9-effector system in mouse embryonic fibroblasts, where we can modulate MSR transcription through the targeting of a dCas9-Repressor or a dCas9-Activator. With this system, we can define a threshold limit of >300-fold deregulation of MSR transcript levels, above which the structural organisation of heterochromatin becomes disrupted. MEF cells expressing MSR RNA above this threshold limit are not viable and the defects in heterochromatin organisation and chromosome segregation cannot be reverted. This study highlights the importance of restricting MSR RNA output to maintain heterochromatin integrity and relates MSR transcript levels to either physiological or pathological conditions. It also reveals that the structural organisation of heterochromatin is governed by the transcriptional chromatin state and associated MSR RNA of the MSR repeats.
小鼠异染色质的特征是具有转录活性的主要卫星重复序列（MSR），并且有人提出MSR RNA有助于异染色质的完整性。我们在小鼠胚胎成纤维细胞中建立了一种诱导型dCas9效应系统，通过靶向dCas9阻遏物或dCas9激活剂来调节MSR转录。利用该系统，我们可以确定MSR转录本水平>300倍失调的阈值，超过该阈值，异染色质的结构组织就会被破坏。表达高于此阈值的MSR RNA的MEF细胞无法存活，异染色质组织和染色体分离的缺陷也无法恢复。这项研究强调了限制MSR RNA输出以维持异染色质完整性的重要性，并将MSR转录本水平与生理或病理状况联系起来。它还揭示了异染色质的结构组织受MSR重复序列的转录染色质状态和相关MSR RNA的调控。
