Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells^1,2,3. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions^4,5,6. Thus, how stem cell activity is molecularly encoded remains unknown. Here we examine the transcriptome, chromatin accessibility and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes⁷. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, we unveil DNA methylation as a promising target for regenerative medicine.

星形胶质细胞是哺乳动物大脑中最丰富的细胞类型，为神经元提供结构和代谢支持，调节突触，并在受伤和疾病后变得反应性。然而，一小部分星形胶质细胞定居在成人大脑的特殊区域，这些星形胶质细胞反而主动产生分化的神经元和神经胶质细胞后代，因此被称为神经干细胞^1,2,3。常见的实质星形胶质细胞和静止神经干细胞具有相似的转录组，尽管它们的功能非常不同^4,5,6。因此，干细胞活性是如何进行分子编码的仍然未知。在这里，我们检查了神经干细胞及其后代的转录组、染色质可及性和甲基化组，以及健康和缺血成年小鼠大脑中纹状体和皮层的星形胶质细胞的转录组、染色质可及性和甲基化组。我们确定了与星形胶质细胞或干细胞功能相关的不同甲基化谱。干细胞功能是由星形胶质细胞基因的甲基化和后来表达的干细胞基因的去甲基化介导的。大脑缺血性损伤诱导纹状体星形胶质细胞干性增加⁷。我们表明，这种反应涉及将星形胶质细胞甲基化组重编程为干细胞甲基化组，如果从头甲基转移酶 DNMT3A 缺失，则不存在。总的来说，我们揭示了 DNA 甲基化是再生医学的一个有前途的靶点。