H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium (scRNA-Seq)

Cell plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is highly stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration. While precise gene expression is needed to control these processes, the regulatory mechanisms that restrict or promote cell plasticity are poorly understood. Here, we use the mouse small intestine as a model system to study cell plasticity. We find that H3K36 methylation reinforces expression of cell type-associated genes to maintain specialized cell identity in intestinal epithelial cells. Depleting H3K36 methylation leads to defects in lineage commitment and activates a plastic, regenerative gene expression signature. Correspondingly, we observe rapid and reversible remodeling of H3K36 methylation following injury-induced regeneration. Together, these data suggest a fundamental role for H3K36 methylation in regulating cell plasticity and regeneration.在发育与体内稳态过程中，细胞可塑性（cell plasticity）不可或缺，其可使干细胞与祖细胞分化生成多种细胞类型。细胞完成分化后，特化细胞的可塑性必须受到限制，以维持组织的完整性与功能。正因如此，在稳态条件下，特化细胞的身份具有高度稳定性；然而，部分组织中的细胞在损伤诱导的再生过程中会重新获得可塑性。尽管精确的基因表达对调控上述过程至关重要，但限制或促进细胞可塑性的调控机制仍未被充分阐明。本研究以小鼠小肠作为模型系统，探究细胞可塑性的调控机制。我们发现，H3K36甲基化（H3K36 methylation）可强化细胞类型相关基因的表达，从而在肠上皮细胞中维持特化细胞的身份。去除H3K36甲基化会引发细胞谱系定型缺陷，并激活具有可塑性的再生基因表达特征。相应地，我们观察到在损伤诱导的再生过程中，H3K36甲基化会发生快速且可逆的重塑。综上，这些数据表明，H3K36甲基化在调控细胞可塑性与再生过程中发挥着基础性作用。