Journal article
MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells
University of Copenhagen1
Department of Biotechnology and Biomedicine, Technical University of Denmark2
Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark3
DTU Proteomics Core, Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark4
Memorial Sloan-Kettering Cancer Center5
Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigenetic protein MPP8 as being essential for ground-state pluripotency.
Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function.
Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together, our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3.
| Language: | English |
|---|---|
| Publisher: | Nature Publishing Group UK |
| Year: | 2021 |
| Pages: | 3034 |
| ISSN: | 20411723 |
| Types: | Journal article |
| DOI: | 10.1038/s41467-021-23308-4 |
| ORCIDs: | 0000-0001-8542-0175 , 0000-0003-1910-4355 , Schoof, Erwin M. , 0000-0003-1260-2247 , 0000-0002-6820-5083 , 0000-0003-1975-6097 and 0000-0002-8990-0843 |
Animals Biochemistry CRISPR-Cas Systems Cell Proliferation Cell biology DNA Methylation Developmental biology Epigenesis, Genetic Gene Knock-In Techniques Genetics HEK293 Cells Histone-Lysine N-Methyltransferase Humans Long Interspersed Nucleotide Elements Mice Molecular biology Mouse Embryonic Stem Cells Mphosph8 protein, mouse Phosphoproteins Pluripotent Stem Cells Q SETDB1 protein, human Science Tumor Suppressor Protein p53
