State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
Weifang People's Hospital, Shandong, 261041, China.
Genome Biol. 2024 May 13;25(1):122. doi: 10.1186/s13059-024-03268-w.
Pluripotent states of embryonic stem cells (ESCs) with distinct transcriptional profiles affect ESC differentiative capacity and therapeutic potential. Although single-cell RNA sequencing has revealed additional subpopulations and specific features of naive and primed human pluripotent stem cells (hPSCs), the underlying mechanisms that regulate their specific transcription and that control their pluripotent states remain elusive.
By single-cell analysis of high-resolution, three-dimensional (3D) genomic structure, we herein demonstrate that remodeling of genomic structure is highly associated with the pluripotent states of human ESCs (hESCs). The naive pluripotent state is featured with specialized 3D genomic structures and clear chromatin compartmentalization that is distinct from the primed state. The naive pluripotent state is achieved by remodeling the active euchromatin compartment and reducing chromatin interactions at the nuclear center. This unique genomic organization is linked to enhanced chromatin accessibility on enhancers and elevated expression levels of naive pluripotent genes localized to this region. In contradistinction, the primed state exhibits intermingled genomic organization. Moreover, active euchromatin and primed pluripotent genes are distributed at the nuclear periphery, while repressive heterochromatin is densely concentrated at the nuclear center, reducing chromatin accessibility and the transcription of naive genes.
Our data provide insights into the chromatin structure of ESCs in their naive and primed states, and we identify specific patterns of modifications in transcription and chromatin structure that might explain the genes that are differentially expressed between naive and primed hESCs. Thus, the inversion or relocation of heterochromatin to euchromatin via compartmentalization is related to the regulation of chromatin accessibility, thereby defining pluripotent states and cellular identity.
具有不同转录特征的胚胎干细胞（ESCs）多能状态会影响 ESC 的分化能力和治疗潜力。虽然单细胞 RNA 测序已经揭示了原始和初始人类多能干细胞（hPSCs）的更多亚群和特定特征，但调节其特定转录和控制其多能状态的潜在机制仍不清楚。
通过高分辨率、三维（3D）基因组结构的单细胞分析，我们在此证明基因组结构的重排与人类 ESC（hESC）的多能状态高度相关。原始多能状态的特点是具有专门的 3D 基因组结构和清晰的染色质区室化，与初始状态明显不同。原始多能状态是通过重塑活性常染色质区室并减少核中心的染色质相互作用来实现的。这种独特的基因组组织与增强的增强子上的染色质可及性和定位在该区域的原始多能基因的高表达水平相关。相反，初始状态表现出混杂的基因组组织。此外，活性常染色质和初始多能基因分布在核周缘，而抑制性异染色质则密集集中在核中心，降低了染色质可及性和原始基因的转录。
我们的数据提供了对原始和初始状态 ESCs 染色质结构的深入了解，并确定了转录和染色质结构修饰的特定模式，这些模式可能解释了原始和初始 hESC 之间差异表达的基因。因此，通过区室化将异染色质反转录或重定位到常染色质与染色质可及性的调节有关，从而定义多能状态和细胞身份。
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