Atherosclerosis is a chronic progressive disease and one of the major causes of cardio-cerebral vascular diseases. Accumulating evidence indicates that endothelial dysfunction is the initiating step in atherosclerosis. The pattern of local blood flow becomes disturbed (low and oscillatory shear stress[OSS]) in the curved or branched segments of the arterial tree, causing endothelial cells (ECs) to exhibit athero-susceptible phenotypes, such as hyperproliferation and inflammation. By contrast, laminar blood flow in the straight parts of the arterial tree (high and unidirectional laminar shear stress[LSS]) causes ECs to act in a way that protects against atherosclerosis. The short isoform of Tet methylcytosine dioxygenase 1 (TET1s) is implicated in early embryonic development, cancer, and the mammalian nervous system. However, whether TET1s expression in ECs can regulate the initiation and development of atherosclerosis has not been explored. In the present study, we provided in vivo and in vitro evidence that atherogenic OSS reduced TET1s expression in ECs. The reduction in TET1s expression in turn induced the inflammatory and proliferative responses of ECs and ultimately led to atherosclerotic lesion formation. In addition, we demonstrated that TET1s prevented the OSS-mediated nuclear translocation of yes-associated protein (YAP) by increasing its phosphorylation at serine 127.These findings support the protective role of TET1s in modulating endothelial athero-susceptible phenotypes and atherogenesis.

Endoplasmic reticulum (ER) membrane protein complex (EMC) is required for the cotranslational insertion of newly synthesized multi-transmembrane proteins. Compromised EMC function in different cell types has been implicated in multiple diseases. Using inducible genetic mouse models, we revealed defects in retinal vascularization upon endothelial cell (EC) specific deletion of Emc1, the largest subunit of EMC. Loss of Emc1 in ECs led to reduced vascular progression and vascular density, diminished tip cell sprouts, and vascular leakage. We then performed an unbiased transcriptomic analysis on human retinal microvascular endothelial cells (HRECs) and revealed a pivotal role of EMC1 in the β-catenin signaling pathway. Further in-vitro and in-vivo experiments proved that loss of EMC1 led to compromised β-catenin signaling activity through reduced expression of Wnt receptor FZD4, which could be restored by lithium chloride (LiCl) treatment. Driven by these findings, we screened genomic DNA samples from familial exudative vitreoretinopathy (FEVR) patients and identified one heterozygous variant in EMC1 that co-segregated with FEVR phenotype in the family. In-vitro expression experiments revealed that this variant allele failed to facilitate the expression of FZD4 on the plasma membrane and activate the β-catenin signaling pathway, which might be a main cause of FEVR. In conclusion, our findings reveal that variants in EMC1 gene cause compromised β-catenin signaling activity, which may be associated with the pathogenesis of FEVR.

Protein arginine methyltransferase 1 (PRMT1), a type I PRMT, is overexpressed in gastric cancer (GC) cells. To elucidate the function of PRMT1 in GC, PRMT1 expression in HGC-27 and MKN-45 cells was knocked down by short hairpin RNA (shRNA) or inhibited by PRMT1 inhibitors (AMI-1 or DCLX069), which resulted in inhibition of GC cell proliferation, migration, invasion, and tumorigenesis in vitro and in vivo.MLX-interacting protein (MLXIP) and Kinectin 1 (KTN1) were identified as PRMT1-binding proteins. PRMT1 recruited MLXIP to the promoter of β-catenin, which induced β-catenin transcription and activated the β-catenin signaling pathway, promoting GC cell migration and metastasis. Furthermore, KTN1 inhibited the K48-linked ubiquitination of PRMT1 by decreasing the interaction between TRIM48 and PRMT1. Collectively, our findings reveal a mechanism by which PRMT1 promotes cell proliferation and metastasis mediated by the β-catenin signaling pathway.