Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells
TL;DR
These findings add a new regulatory layer of chromatin state in rDNA of stem cells, and reveal a previously unrecognized phenotypic consequence of defective RiBi in ESCs.
Abstract
Embryonic stem cells (ESCs) exhibit a hyperactive chromatin state at ribosomal RNA (rRNA) genes, which not only plays roles in active rRNA synthesis and ribosome biogenesis (RiBi), but also links to genome architecture. However, how this active chromatin state is maintained in ESCs remains poorly understood. Here, we identify Tcf15, a mouse ESC-specific factor, as a novel regulator of ribosomal DNA (rDNA) chromatin state. Tcf15 localizes to the nucleolus, binds the coding region of rRNA genes, and independently recruits epigenetic modifiers—either Tet2 or Rbbp5 (a core component of H3K4 methyltransferases)—to promote an active chromatin configuration. Depletion of Tcf15 increases DNA methylation and H3K27me3 levels at rDNA. Intriguingly, the Tcf15-Rbbp5 axis ensures precursor rRNA transcription and RiBi, whereas the Tcf15-Tet2 axis is not involved in rRNA synthesis. Ribosome profiling further revealed compromised translation of a subset of mRNAs involved in DNA replication, damage response, and repair. Consequently, Tcf15- or Rbbp5-deficient ESCs exhibit severe genomic instability. Our findings add a new regulatory layer of chromatin state in rDNA of stem cells, and reveal a previously unrecognized phenotypic consequence of defective RiBi in ESCs.