H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium [regen_rnaseq_mouse]. H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium [regen_rnaseq_mouse]

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. Overall design: RNA-sequencing for WT mice at 0, 3 and 5 days after irradiation, 2 biological replicates each.

细胞可塑性（cell plasticity）在发育与稳态过程中不可或缺，可由干细胞及祖细胞分化产生多种细胞类型。细胞完成分化后，其可塑性需受到严格限制，以维持特化细胞的组织完整性与生理功能。正因如此，稳态条件下特化细胞的细胞身份高度稳定；但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。尽管精准调控基因表达（gene expression）是控制这些过程的关键，但限制或促进细胞可塑性的调控机制仍有待深入解析。
本研究以小鼠小肠为模型系统探究细胞可塑性，发现H3K36甲基化（H3K36 methylation）可强化细胞类型相关基因的表达，从而维持肠上皮细胞的特化细胞身份。抑制H3K36甲基化会导致谱系定型缺陷，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。
综合以上实验结果，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。
整体实验设计：对野生型（WT）小鼠在辐照后第0、3、5天进行RNA测序（RNA-sequencing），每组设置2个生物学重复。