Abstract
SETDB1 (SET Domain Bifurcated histone lysine methyltransferase 1) is a key lysine methyltransferase (KMT) required in embryonic stem cells (ESCs), where it silences transposable elements and DNA repeats via histone H3 lysine 9 tri-methylation (H3K9me3), independently of DNA methylation. The H3K9 methylation reader M-Phase Phosphoprotein 8 (MPP8) is highly expressed in ESCs and germline cells. Although evidence of a cooperation between H3K9 KMTs and MPP8 in committed cells has emerged, the interplay between H3K9 methylation writers and MPP8 in ESCs remains elusive. Here, we show that MPP8 interacts physically and functionally with SETDB1 in ESCs. Indeed, combining biochemical, transcriptomic and genomic analyses, we found that MPP8 and SETDB1 co-regulate a significant number of common genomic targets, especially the DNA satellite repeats. Together, our data point to a model in which the silencing of a class of repeated sequences in ESCs involves the cooperation between the H3K9 methylation writer SETDB1 and its reader MPP8.
Highlights
Post-translational modifications of histones play key roles in DNA functions in the chromatin context
Our results suggest a new regulatory mechanism for repeated sequences in mouse embryonic stem cells (mESCs) which involves the cooperation between the major H3K9 methylation writer SETDB1 and its reader M-Phase Phosphoprotein 8 (MPP8)
In light of the co-immunoprecipitation and Chromatin Immunoprecipitation (ChIP)-seq results described above, showing a physical interaction between MPP8 and SETDB1 and genomic co-binding in mESCs, we further investigated the possible functional interplay between MPP8 and SETDB1
Summary
Post-translational modifications of histones play key roles in DNA functions in the chromatin context. The main location of H3K9 methylation is on heterochromatin and more generally on repetitive elements, such as the major and minor satellite repeats in the mouse genome [1]. Protein 1, called MCAF1), which is necessary for the conversion of H3K9me to H3K9me3 [3] This ability of SETDB1 to establish the three H3K9 methylation levels makes this KMT important. We have combined biochemical and genomic strategies to get insights on the functions of the major H3K9 reader MPP8 in mESCs, where H3K9 methylation plays key roles in the non-coding genome and transposable elements silencing compared to committed cells. Our results suggest a new regulatory mechanism for repeated sequences in mESCs which involves the cooperation between the major H3K9 methylation writer SETDB1 and its reader MPP8
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