Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
Cells. 2024 Jun 25;13(13):1095. doi: 10.3390/cells13131095.
Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging.
We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells.
We found hyperexpression of , , and and decreased expression of , , , , , , and in the astrocytes of patients with autism, along with DNA hypomethylation of , , and gene promoters and a decrease in promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, and expression trended alike. While promoter was hypermethylated in neurons, and promoters were hypomethylated and exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of and promoter regions, but DNA hypermethylation of and promoters in autism.
Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics.
过度的炎症反应和氧化应激是自闭症中公认的分子发现，这些过程可以影响或受表观遗传景观的影响。尽管如此，仍然缺乏有效的治疗方法，因为针对个体化治疗的患者特异性大脑分子标志物仍然具有挑战性。
我们使用自闭症患者和对照组的 iPSC 衍生神经元和星形胶质细胞（每组 5 个）来检查它们是否复制了自闭症的死后大脑表达/表观遗传改变。此外，还分析了 10 个死后脑组织样本（每组 5 个）的 DNA 甲基化，以研究受 PSC 衍生细胞影响的基因。
我们发现自闭症患者的星形胶质细胞中 、 、 、 和 表达过度，而 、 、 、 、 、 和 表达降低，同时自闭症患者的星形胶质细胞中 、 、 、 和 基因启动子的 DNA 去甲基化和 启动子 5-羟甲基化减少。在神经元中， 和 表达趋势相似。虽然 启动子在神经元中呈高甲基化，但 、 启动子呈低甲基化， 表现出增加的启动子 5-羟甲基化。我们还发现自闭症患者的神经元树突分支、棘突大小、生长速度和迁移减少，但星形胶质细胞体积增大，生长速度降低。在死后脑组织样本中，我们发现自闭症患者的 、 启动子区域的 DNA 去甲基化，但 、 启动子的 DNA 高甲基化。
iPSC 衍生细胞中与自闭症相关的表达/表观遗传改变复制了文献中报道的改变，使其成为研究疾病发病机制或患者特异性治疗的合适替代物。
