Lgr5+ intestinal stem cells (ISCs) drive the fast renewal of intestinal epithelium. Several signaling pathways have been shown to regulate ISC fates. However, it is unclear what are the essential signals to sustain the ISC self-renewal. Using genetic and single-cell RNA-sequencing approaches, we observed the critical roles of BMP and stromal cells in maintaining ISC self-renewal and epithelial homeostasis. We have also constructed a spatiotemporal transcriptomic landscape of the mouse stomach and intestine during embryonic day E9.5-E15.5. The regionalization and heterogeneity of both the epithelium and mesenchyme could be traced back to E9.5. The spatiotemporal distributions of cell clusters and the mesenchymal-epithelial interaction analysis indicate that a coordinated development of the epithelium and mesenchyme contribute to the stomach regionalization, intestine segmentation and villus formation.

The genome of eukaryotes undergoes profound epigenetic modifications to allow for development and adaptation. The biological significance and mechanisms of the cytosine base modifications are incompletely understood. We and others found that 5-methylcytosine (5mC), a prominent modified base present in mammalian genomic DNA, can be oxidized stepwise and demethylated in mouse by the Ten-Eleven- Translocation (Tet) family of dioxygenases. Deficiency in Tet enzymes impedes demethylation and activation of developmental genes such as Oct4 and Lefty1 in the embryo, leading to lethality. Interestingly, oocytes lacking Tet are unable to reprogram injected somatic cell nuclei. Additionally, mouse embryonic fibroblasts (MEFs) deficient in Tet cannot be reprogrammed into iPSCs by Yamanaka factors. Tet-mediated oxidative demethylation is required for cell fate determination in embryonic development as well as for cell reprogramming.

tRNA分子在蛋白合成中起着转运氨基酸的作用，每种tRNA由一种或多种tRNA(isoacceptors)转运，而每种tRNA可由多个tRNA基因(tDNA)转录产生。但近年的研究表明，成熟的tRNA分子可代谢产生不同大小的片段，它们可抑制或促进某些 mRNA的翻译、降低或增强某些 mRNA的稳定性。我们在斑马鱼胚胎中的研究发现，胚胎中富含许多 tRNA 从反密码子处切开而产生的、长度为 30-37nt、源于 5’ 端半截的 5’tRFl，其中 5’tRFlGly/GCC和 5’tRFlGlu/CTC尤其显著。用吗啉环修饰的反义寡核苷酸抑制胚胎中 5’tRFlGly/GCC 或 5’ tRFlGlu/CTC 的作用，均导致胚胎发育阻滞在原肠期，但给胚胎同时注射对应的、适当折叠的外源全长 tRNA可以挽救发育阻滞表型;另一方面，敲降5’tRFlGly/GCC或 5’tRFlGlu/CTC 还导致对应的tDNAGly/GCC或tDNAGlu/CTC的表达量下降，而过表达其模拟物可促进对应tRNA的表达，说明5’tRFl正调控对应tDNA的转录。R-loop 分析表明，胚胎中许多全长tRNA和 5‘tRFl均可与tDNA 模板链形成 RNA:DNA双链。

表观遗传是由非DNA序列改变所致的可遗传的表型改变，这些改变主要通过对基因转录或翻译过程的调控影响基因功能和表型，包括 DNA 甲基化、组蛋白修饰、染色体重塑和非编码RNA调控等。表观遗传调控在发育、衰老、免疫调节等生理过程，以及肿瘤、神经系统疾病、代谢性疾病等多种疾病的发生发展中发挥重要作用。近年来，我国学者在表观遗传领域取得了多项重要研究成果，本汇报将从基因选 择性转录表达的调控(DNA修饰、组蛋白修饰、染色质重塑)和基因 转录后的调控(RNA修饰、非编码RNA)几个方面，综述我国学者近年在表观遗传领域发表的与生命健康相关的重要学术成果，并对表观遗传学在临床的应用前景进行展望。