Dot1l cooperates with Npm1 to repress endogenous retrovirus MERVL in embryonic stem cells

Abstract

Dot1l is a histone methyltransferase without a SET domain and is responsible for H3K79 methylation, which marks active transcription. In contradiction, Dot1l also participates in silencing gene expression. The target regions and mechanism of Dot1l in repressing transcription remain enigmatic. Here, we show that Dot1l represses endogenous retroviruses in embryonic stem cells (ESCs). Specifically, the absence of Dot1l led to the activation of MERVL, which is a marker of 2-cell-like cells. In addition, Dot1l deletion activated the 2-cell-like state and predisposed ESCs to differentiate into trophectoderm lineage. Transcriptome analysis revealed activation of 2-cell genes and meiotic genes by Dot1l deletion. Mechanistically, Dot1l interacted with and co-localized with Npm1 on MERVL, and depletion of Npm1 similarly augmented MERVL expression. The catalytic activity and AT-hook domain of Dot1l are important to suppress MERVL. Notably, Dot1l-Npm1 restricts MERVL by regulating protein level and deposition of histone H1. Furthermore, Dot1l is critical for Npm1 to efficiently interact with histone H1 and inhibit ubiquitination of H1 whereas Npm1 is essential for Dot1l to interact with MERVL. Altogether, we discover that Dot1l represses MERVL through chaperoning H1 by collaborating with Npm1. Importantly, our findings shed light on the non-canonical transcriptional repressive role of Dot1l in ESCs.

Nucleophosmin 1 cooperates with the methyltransferase DOT1L to preserve peri-nucleolar heterochromatin organization by regulating H3K27me3 levels and DNA repeats expression

“…Our findings of a non-canonical role of DOT1L in DNA repeats repression are supported by the recent discoveries of Zhao et al [ 80 ], who showed that DOT1L cooperates with NPM1 to silence MERVL expression in mESC. However, repression of MERVL in mESC required DOT1L enzymatic activity.…”

An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system

“…Many methyltransferase-independent roles for DOT1L have also been reported. These include transcriptional initiation, nucleosome remodelling, histone exchange and H2B ubiquitination (67)(68)(69)(70)(71). In addition, DOT1L is implicated in the DNA damage response pathway by promoting the repair of double-strand breaks (8,19,72).…”

Regulation of endogenous retroviruses in murine embryonic stem cells and early embryos

“…Histone H1 and its variants compact the nucleosome array into heterochromatin. Recently, it was discovered that histone H1 variants and Nucleophosmin 1 (Npm1), a histone chaperone of H1, are involved in repressing ERVs in ESCs ( Zhao et al., 2023b ). The loss of histone H1 variants (H1.2, H1.3, and H1.4) mainly activated the expression of the ERVK family and MERVL ( Zhao et al., 2023b ).…”

“…Recently, it was discovered that histone H1 variants and Nucleophosmin 1 (Npm1), a histone chaperone of H1, are involved in repressing ERVs in ESCs ( Zhao et al., 2023b ). The loss of histone H1 variants (H1.2, H1.3, and H1.4) mainly activated the expression of the ERVK family and MERVL ( Zhao et al., 2023b ). Npm1 represses MERVL by regulating the protein stability of histone H1 variants.…”

“…Npm1 represses MERVL by regulating the protein stability of histone H1 variants. The interaction between Npm1 and histone H1 is regulated by the histone methyltransferase disruptor of telomeric silencing 1-like (Dot1l), which is co-enriched with Npm1 in MERVL ( Zhao et al., 2023b ). Therefore, Dot1l is also necessary for the repression of ERVs, including MERVL.…”