Yan Jielin, Luo Renhe, Rosen Bess P, Liu Dingyu, Wong Wilfred, Leslie Christina S, Huangfu Danwei
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
Stem Cell Reports. 2025 Jun 10;20(6):102511. doi: 10.1016/j.stemcr.2025.102511. Epub 2025 May 29.
Human embryonic stem cells (hESCs) are notable for their ability to self-renew and to differentiate into all tissue types in the body. NANOG is a core regulator of hESC identity, and dynamic control of its expression is crucial to maintain the balance between self-renewal and differentiation. Transcriptional regulation depends on enhancers, but NANOG enhancers in hESCs are not well characterized. Here, we report two NANOG enhancers discovered from a CRISPR interference screen in hESCs. Deletion of a single copy of either enhancer significantly reduced NANOG expression, compromising self-renewal and increasing differentiation propensity. Interestingly, these two NANOG enhancers are involved in a tandem duplication event found in certain primates including humans but not in mice. However, the duplicated counterparts do not regulate NANOG expression. This work expands our knowledge of functional enhancers in hESCs and highlights the sensitivity of the hESC state to the dosage of core regulators and their enhancers.
人类胚胎干细胞（hESCs）以其自我更新和分化为体内所有组织类型的能力而闻名。NANOG是hESC特性的核心调节因子，其表达的动态控制对于维持自我更新和分化之间的平衡至关重要。转录调控依赖于增强子，但hESCs中的NANOG增强子尚未得到充分表征。在这里，我们报告了从hESCs的CRISPR干扰筛选中发现的两个NANOG增强子。删除任何一个增强子的单拷贝都会显著降低NANOG表达，损害自我更新并增加分化倾向。有趣的是，这两个NANOG增强子参与了在包括人类在内的某些灵长类动物中发现的串联重复事件，但在小鼠中未发现。然而，重复的对应物并不调节NANOG表达。这项工作扩展了我们对hESCs中功能增强子的认识，并突出了hESC状态对核心调节因子及其增强子剂量的敏感性。
