Project description:JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2-mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown sequence-specificity of the mRNA 3' processing machinery.
Project description:Multipotent and pluripotent stem cells have significant potential as sources for cell replacement therapies. However, the low yield and quality of in vitro differentiated cells produced from various stem cell sources presents a significant limitation for therapeutic applications. The most mature use of these stem cell products is in the field of transfusion medicine, where stem cell-derived red blood cells (RBCs) have clinically-proven potential as alternative transfusion products. To improve upon current approaches for RBC production, we used insight from both common and rare human genetic variation of blood counts to focus on the SH2B3 gene. By producing loss of function of SH2B3 using targeted knockdown and genome editing approaches in human hematopoietic stem and progenitor cells, as well as human pluripotent stem cells, we are able to significantly improve both the quality and yield of in vitro derived RBCs. We illustrate how insight from human genetic variation can assist in the development of broadly applicable approaches that have tremendous value for regenerative medicine.
Project description:Purpose: To search candidate synergized compounds from Chinese herbal medicine used in RA therapy Methods: Candidate synergized compounds were searched based on multi-information integrative approaches. In vivo experiment in collagen induced arthritis rat was then carried out to evaluate the efficacy and synergism of compounds combination treatment. RNA sequencing and IPA were used to investigate the synergized mechanism of combination treatment. Results: We found a pair of compound combination which could alleviate the symptom of CIA rats. RNA sequencing and IPA analysis revealed that the synergistic mechanism of combination treatment was related to several canonical signaling pathways and key targets LTA, CD83 and SREBF1. Conclusion: A pair of compound combination has been found. RNA sequencing and IPA analysis revealed that the synergistic mechanism of combination treatment was related to several canonical signaling pathways and key targets.
2021-09-20 | GSE148598 | GEO
Project description:Panorama Medicine drug compound screening 1 (batch 3)
| PRJNA1071491 | ENA
Project description:Panorama Medicine drug compound screening 1 (batch 1)