Computational Biology & Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
Group of Computational Biology & Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain.
Epigenomics. 2018 Feb;10(2):149-174. doi: 10.2217/epi-2017-0098. Epub 2018 Jan 16.
Disclosing the mechanisms that regulate reprogramming memory.
MATERIALS & METHODS: We established computational procedure to find DNA methylation somatic memory sites (SMSs) at single CpGs and integrated them with genomics, epigenomics, transcriptomics and imprinting information.
RESULTS & CONCLUSION: Reprogramming memory persists at late passages in low methylated regions. Contrarily to hypomethylated, hypermethylated SMSs occur at evolutionary conserved sites overlapping active transcription loci in dynamic chromatin regions. The epigenetic-memory molecular origin is the expression of source-cell transcription factors protecting hypomethylated SMSs in euchromatin from de novo methylation, keeping source-cell lineage-specific loci in induced pluripotent stem (iPS) cells incompletely silenced. Sites in lineage-specific genes of different-from-those-of-the-source-cell lineages remain hypermethylated in heterochromatin regions becoming permanently silenced. SMSs cause differential expression between iPS cells and embryonic stem cells through two mechanisms: 'epigenetic/expression memory rule', the DNA unreprogramming methylation status coupled with chromatin states induces differentially expressed genes. 'Imprinting control', the change of DNA methylation status in imprinting control regions induces differential expression of imprinted genes.
揭示调控重编程记忆的机制。
我们建立了计算程序，以在单个 CpG 上找到 DNA 甲基化体细胞记忆位点 (SMSs)，并将其与基因组学、表观基因组学、转录组学和印记信息整合在一起。
重编程记忆在低甲基化区域的晚期阶段仍然存在。与低甲基化相反，高甲基化 SMSs 发生在进化保守的位点上，与动态染色质区域中的活跃转录基因座重叠。表观遗传记忆的分子起源是源细胞转录因子的表达，它保护常染色质中低甲基化 SMS 免受从头甲基化，使诱导多能干细胞 (iPS) 细胞中的源细胞谱系特异性基因座不完全沉默。不同来源细胞谱系的谱系特异性基因中的位点在异染色质区域中仍保持高甲基化，从而被永久沉默。SMS 通过两种机制导致 iPS 细胞和胚胎干细胞之间的差异表达：“表观遗传/表达记忆规则”，与染色质状态相关联的 DNA 去重编程甲基化状态诱导差异表达基因。“印记控制”，印记控制区域中 DNA 甲基化状态的变化诱导印记基因的差异表达。
