Mphosph8-KO Mouse

Mphosph8, also known as MPP8 (M-phase phosphoprotein 8), is a component of the human silencing hub (HUSH) complex. It plays a crucial role in epigenetic regulation, particularly in the silencing of long interspersed element-1 (LINE-1 or L1) retrotransposons [1,2,4]. This silencing function is associated with maintaining genome stability and is involved in various biological processes. Genetic models, such as gene knockout mouse models, can be valuable for further exploring its functions.

In acute myeloid leukemia (AML), MPP8 is an AML-selective dependency. Loss of MPP8 inhibits AML development by reactivating L1s, which in turn induces the DNA damage response and cell cycle exit [1]. In medullary thyroid cancer (MTC), depletion of MPHOSPH8 significantly inhibits cell proliferation, leading to G0/G1 phase cell cycle arrest and apoptosis, suggesting it promotes cell proliferation in MTC [3]. In mice, genetic inactivation of Mphosph8 in the nervous system leads to increased brain size, altered brain architecture, and behavioral changes, as MPP8 suppresses the repetitive-like protocadherin gene cluster in an H3K9me3-dependent manner [5].

In summary, Mphosph8 is essential for the silencing of L1 retrotransposons through its role in the HUSH complex. Its function is critical in multiple disease areas, including AML, MTC, and in maintaining normal brain development. Studies using gene knockout mouse models have been instrumental in revealing these functions, deepening our understanding of the biological processes and disease mechanisms associated with Mphosph8.

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. 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/

5. 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/