Alternative titles; symbols
HGNC Approved Gene Symbol: MPHOSPH8
Cytogenetic location: 13q12.11 Genomic coordinates (GRCh38) : 13:19,633,659-19,673,441 (from NCBI)
Using N-terminally truncated RANBPM (RANBP9; 603854) as bait in a yeast 2-hybrid screen of a human lymphocyte cDNA library, Umeda et al. (2003) obtained a partial cDNA encoding the C-terminal half of MPHOSPH8, which they called TWA3.
Tchasovnikarova et al. (2015) used a nonlethal forward genetic screen in near-haploid KBM7 cells to search for genes required for epigenetic repression in human cells. The authors identified the HUSH (human silencing hub) complex, comprising 3 proteins, TASOR (FAM208A; 616493), MPP8, and periphilin (PPHLN1; 608150). This complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased trimethylation of histone-3 on lys9 (H3K9me3) both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Tchasovnikarova et al. (2015) concluded that their results suggested that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 (604396) is required for further H3K9me3 deposition to maintain transcriptional silencing.
To provide a genomewide survey of genes involved in the control of L1 retrotransposition (see LRE1, 151626), Liu et al. (2018) used CRISPR-Cas9 screening strategies in 2 distinct human cell lines and identified functionally diverse genes that either promote or restrict L1 retrotransposition. These genes, which are often associated with human diseases, control the L1 life cycle at the transcriptional or the posttranscriptional level in a manner that can depend on the endogenous L1 nucleotide sequence, underscoring the complexity of L1 regulation. The authors further investigated the restriction of L1 by the protein MORC2 (616661) and by the HUSH complex subunits MPP8 and TASOR. HUSH and MORC2 can selectively bind evolutionarily young, full-length L1s located within transcriptionally permissive euchromatic environments, and promote deposition of H3K9me3 for transcriptional silencing. These silencing events often occur within introns of transcriptionally active genes, and lead to the downregulation of host gene expression in a HUSH-, MORC2-, and L1-dependent manner.
Zhu et al. (2018) performed a genomewide CRISPR-Cas9 screen for genes that are required for silencing an integrase-deficient MLV-GFP reporter virus to explore the mechanisms responsible for repression of unintegrated viral DNAs in human cells. This screen identified the DNA-binding protein NP220 (614349); the 3 proteins (MPP8, TASOR, and PPHLN1) that comprise the HUSH complex, which silences proviruses in heterochromatin and retrotransposons; the histone methyltransferase SETDB1; and other host factors that are required for silencing. Further tests by chromatin immunoprecipitation showed that NP220 is the key protein that recruits the HUSH complex, SETDB1, and the histone deacetylases HDAC1 (601241) and HDAC4 (605314) to silence the unintegrated retroviral DNA. Knockout of NP220 accelerated the replication of retroviruses. Zhu et al. (2018) concluded that their experiments identified the molecular machinery that silences extrachromosomal retroviral DNA.
The International Radiation Hybrid Mapping Consortium mapped the MPHOSPH8 gene to chromosome 13 (RH66674).
Liu, N., Lee, C. H., Swigut, T., Grow, E., Gu, B., Bassik, M. C., Wysocka, J. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553: 228-232, 2018. [PubMed: 29211708] [Full Text: https://doi.org/10.1038/nature25179]
Tchasovnikarova, I. A., Timms, R. T., Matheson, N. J., Wals, K., Antrobus, R., Gottgens, B., Dougan, G., Dawson, M. A., Lehner, P. J. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348: 1481-1485, 2015. [PubMed: 26022416] [Full Text: https://doi.org/10.1126/science.aaa7227]
Umeda, M., Nishitani, H., Nishimoto, T. A novel nuclear protein, Twa1, and Muskelin comprise a complex with RanBPM. Gene 303: 47-54, 2003. [PubMed: 12559565] [Full Text: https://doi.org/10.1016/s0378-1119(02)01153-8]
Zhu, Y., Wang, G. Z., Cingoz, O., Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564: 278-282, 2018. [PubMed: 30487602] [Full Text: https://doi.org/10.1038/s41586-018-0750-6]