澳大利亚西澳大利亚大学Ryan Lister和莫纳什大学Jose M. Polo团队合作发现，瞬时初始重编程在功能和表观遗传上纠正了人类诱导多能干细胞(hiPS细胞)。2023年8月16日，国际知名学术期刊《自然》发表了这一成果。

他们通过对人类体细胞向hiPS细胞的启动和初始重编程进行全基因组DNA甲基化分析，表征了这些表观遗传差异的持久性和出现。他们发现重编程诱导的表观遗传畸变在启动重编程的中途出现，而DNA去甲基化在初始重编程的早期就开始了。利用这些知识，他们开发了一种模拟胚胎表观遗传重置的瞬时初始处理(TNT)重编程策略。他们发现，hiPS细胞的表观遗传记忆集中在由H3K9me3、lamin-B1和异常CpH甲基化标记的来源依赖性抑制染色质细胞中。TNT重编程将这些结构域重新配置为类似人胚胎干细胞(hES)细胞的状态，并且不会破坏基因组印迹。

利用等基因系统，他们证明TNT重编程可以纠正传统hiPS细胞中的转座因子过表达和差异基因表达，并且TNT重编程的hiPS和hES细胞表现出相似的分化效率。此外，TNT重编程增强了来自多种细胞类型的hiPS细胞的分化。因此，TNT重编程纠正了表观遗传记忆和畸变，产生了比传统hiPS细胞在分子和功能上更类似于hES细胞的hiPS细胞。他们预见TNT重编程将成为生物医学和治疗应用的新标准，并为研究表观遗传记忆提供一个新的系统。

据悉，当细胞被重编程为hiPS细胞时，细胞经历了一个主要的表观基因组重构。然而，hiPS细胞与hES细胞的表观基因组存在显著差异，从而影响了hiPS细胞的功能。这些差异包括表观遗传记忆和重编程过程中出现的畸变，其机制尚不清楚。

附：英文原文

Title: Transient naive reprogramming corrects hiPS cells functionally and epigenetically

Author: Buckberry, Sam, Liu, Xiaodong, Poppe, Daniel, Tan, Jia Ping, Sun, Guizhi, Chen, Joseph, Nguyen, Trung Viet, de Mendoza, Alex, Pflueger, Jahnvi, Frazer, Thomas, Vargas-Landn, Dulce B., Paynter, Jacob M., Smits, Nathan, Liu, Ning, Ouyang, John F., Rossello, Fernando J., Chy, Hun S., Rackham, Owen J. L., Laslett, Andrew L., Breen, James, Faulkner, Geoffrey J., Nefzger, Christian M., Polo, Jose M., Lister, Ryan

Issue&Volume: 2023-08-16

Abstract: Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function1,2,3,4,5,6,7,8. These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory.

DOI: 10.1038/s41586-023-06424-7

Source: https://www.nature.com/articles/s41586-023-06424-7