RNAseq analysis of whole Guts over expressing LaminDm0 or GFP in Enterocytes

A hallmark of aging-related disease such as neurodegeneration, metabolic disorders, and cancer is the inability of differentiated cells to maintain their identity. In a search for identity regulators, we found that transcription factor Hey supervises the identity of differentiated enterocytes (ECs) in the adult Drosophila midgut. Lineage tracing of ECs established that Hey-deficient ECs lose differentiated identity, are unable to maintain their unique nuclear organization, and exhibit pathological reprograming. Orchestrating this organization, Hey specifies and maintains enhancer activity and nuclear lamins expression, remodeling nuclear architecture from a stem-cell configuration into a differentiated one. Moreover, maintaining this configuration of nuclear lamins is key for cell identity, and lamin misexpression overrides cell identities. At the tissue level, loss of Hey or expression of stem cell-related lamin (LamDm0) in ECs resulted in mis-differentiation, impaired epithelial integrity, and reduced organismal survival. Thus, a single transcription factor concomitantly supervises chromatin and nuclear organization, safeguarding cell identity

神经退行性疾病、代谢紊乱及癌症等衰老相关疾病的标志性特征，在于分化细胞无法维持自身细胞身份。在筛选细胞身份调控因子的研究中，我们发现转录因子Hey可调控成年果蝇中肠内分化肠上皮细胞（enterocytes, ECs）的细胞身份。对ECs的谱系示踪实验证实，Hey缺失的ECs会丧失分化后的细胞身份，无法维持其特有的细胞核组织结构，并表现出病理性重编程。Hey通过调控该细胞核组织结构，特异性确立并维持增强子活性与核纤层蛋白（nuclear lamins）的表达，将细胞核架构从干细胞状态重塑为分化细胞状态。此外，维持核纤层蛋白的这种表达构型是维持细胞身份的关键，而核纤层蛋白的异常表达会颠覆细胞身份。在组织层面，ECs中Hey的缺失或干细胞相关核纤层蛋白（LamDm0）的表达，会引发分化异常、上皮完整性受损，并降低机体存活率。综上，单一转录因子可同时调控染色质与细胞核架构，从而保障细胞身份的稳定维持。