Mphosph8-KO Mouse

Mphosph8, also known as MPP8, is a component of the human silencing hub (HUSH) complex. It plays a crucial role in the epigenetic silencing of transposable elements, particularly long interspersed element-1 (LINE-1 or L1) retrotransposons. This silencing is vital for genome stability as aberrant L1 activation can lead to genetic variability. The HUSH complex, with Mphosph8, is involved in pathways related to histone H3 Lys9 trimethylation (H3K9me3) deposition for transcriptional silencing, and is associated with multiple biological processes and disease-related pathways [2,4,5,6,7,8].

Genetic inactivation of Mphosph8 in the nervous system of mice led to increased brain size, altered brain architecture, and behavioral changes. In both mouse brains and human cerebral organoids, MPP8 suppresses the repetitive-like protocadherin gene cluster in an H3K9me3-dependent manner, revealing its role in brain development and neuronal individuality [9]. In acute myeloid leukemia (AML), MPP8 is an AML-selective dependency. Loss of MPP8 inhibits AML development by reactivating L1s, which then induce the DNA damage response and cell cycle exit [1]. In medullary thyroid cancer (MTC), depletion of MPHOSPH8 significantly inhibited cell proliferation, leading to G0/G1 phase cell cycle arrest and apoptosis, suggesting it promotes cell proliferation in MTC [3].

In summary, Mphosph8 is essential for the epigenetic silencing of transposable elements, especially L1 retrotransposons, through its role in the HUSH complex. Studies using gene-knockout models in mice have revealed its significance in diseases such as AML and MTC, as well as in brain development. Understanding Mphosph8's function provides insights into the mechanisms of genome stability, disease development, and potential therapeutic targets for these diseases.

References:

1. Gu, Zhimin, Liu, Yuxuan, Zhang, Yuannyu, Abrams, John M, Xu, Jian. 2021. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. In Nature genetics, 53, 672-682. doi:10.1038/s41588-021-00829-8. https://pubmed.ncbi.nlm.nih.gov/33833453/

2. Liu, Nian, Lee, Cameron H, Swigut, Tomek, Bassik, Michael C, Wysocka, Joanna. 2017. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. In Nature, 553, 228-232. doi:10.1038/nature25179. https://pubmed.ncbi.nlm.nih.gov/29211708/

3. Li, Peiyong, Yang, Weiping, Shen, Baiyong, Li, Hongwei, Yan, Jiqi. 2016. Lentivirus-mediated silencing of MPHOSPH8 inhibits MTC proliferation and enhances apoptosis. In Oncology letters, 11, 4117-4122. doi:. https://pubmed.ncbi.nlm.nih.gov/27313751/

4. Li, Zhiming, Duan, Shoufu, Hua, Xu, Goff, Stephen P, Zhang, Zhiguo. 2023. Asymmetric distribution of parental H3K9me3 in S phase silences L1 elements. In Nature, 623, 643-651. doi:10.1038/s41586-023-06711-3. https://pubmed.ncbi.nlm.nih.gov/37938774/

5. Rodríguez, Tomás C, Yurkovetskiy, Leonid, Nagalekshmi, Karthika, Sontheimer, Erik J, Luban, Jeremy. 2024. PRC1.6 localizes on chromatin with the human silencing hub (HUSH) complex for promoter-specific silencing. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.07.12.603173. https://pubmed.ncbi.nlm.nih.gov/39026796/

6. Müller, Iris, Moroni, Ann Sophie, Shlyueva, Daria, Huang, Chang, Helin, Kristian. 2021. MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells. In Nature communications, 12, 3034. doi:10.1038/s41467-021-23308-4. https://pubmed.ncbi.nlm.nih.gov/34031396/

7. Zhu, Yiping, Wang, Gary Z, Cingöz, Oya, Goff, Stephen P. 2018. NP220 mediates silencing of unintegrated retroviral DNA. In Nature, 564, 278-282. doi:10.1038/s41586-018-0750-6. https://pubmed.ncbi.nlm.nih.gov/30487602/

8. Tchasovnikarova, Iva A, Timms, Richard T, Matheson, Nicholas J, Dawson, Mark A, Lehner, Paul J. 2015. GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. In Science (New York, N.Y.), 348, 1481-1485. doi:10.1126/science.aaa7227. https://pubmed.ncbi.nlm.nih.gov/26022416/

9. Hagelkruys, Astrid, Horrer, Marion, Taubenschmid-Stowers, Jasmin, Knoblich, Jürgen A, Penninger, Josef M. 2022. The HUSH complex controls brain architecture and protocadherin fidelity. In Science advances, 8, eabo7247. doi:10.1126/sciadv.abo7247. https://pubmed.ncbi.nlm.nih.gov/36332029/