Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Bioinformatics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17842-17853. doi: 10.1073/pnas.2002427117. Epub 2020 Jul 15.
Stem cells are capable of unlimited proliferation but can be induced to form brain cells. Factors that specifically regulate human development are poorly understood. We found that human stem cells expressed high levels of the envelope protein of an endogenized human-specific retrovirus (HERV-K, HML-2) from loci in chromosomes 12 and 19. The envelope protein was expressed on the cell membrane of the stem cells and was critical in maintaining the stemness via interactions with CD98HC, leading to triggering of human-specific signaling pathways involving mammalian target of rapamycin (mTOR) and lysophosphatidylcholine acyltransferase (LPCAT1)-mediated epigenetic changes. Down-regulation or epigenetic silencing of HML-2 resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. Thus HML-2 regulation is critical for human embryonic and neurodevelopment, while it's dysregulation may play a role in tumorigenesis and neurodegeneration.
干细胞具有无限增殖的能力，但可以被诱导形成脑细胞。目前人们对特定调节人类发育的因素知之甚少。我们发现，人类干细胞在 12 号和 19 号染色体上的特定位置表达高水平的内源性人类特异性逆转录病毒（HERV-K，HML-2）的包膜蛋白。该包膜蛋白在干细胞的细胞膜上表达，通过与 CD98HC 的相互作用，对维持干细胞特性至关重要，从而触发涉及雷帕霉素靶蛋白（mTOR）和溶血磷脂酰胆碱酰基转移酶（LPCAT1）介导的表观遗传变化的人类特异性信号通路。下调或表观遗传沉默 HML-2 会导致干细胞集落解离，并沿神经元途径增强分化。因此，HML-2 的调控对人类胚胎和神经发育至关重要，而其失调可能在肿瘤发生和神经退行性变中起作用。
