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PICB Institute Seminar: by Sirui Zhang & Xuan Cao, 3rd, April, 2019
Authors:PICB    Time:2019-04-01    Read:69

Time : 16:00-17:30 pm, Apr.3(Wednesday)

Venue: Room 300, SIBS Main Building, Yueyang Road 320

HostPICB Student Group

 

Speaker1:  Sirui Zhang

Title: Systematic study of cancer-associated alternative splicing

 

Abstract: Alternative splicing (AS) influences the expression of most genes in eukaryotic cells and is tightly regulated in both special and temporal fashion. The dysregulation of AS is one of the molecular hallmarks of cancer, with hundreds of AS events shifted in cancer cells. Therefore, it is very important to systematically explore cancer-associated alternative splicing.
The gene encoding splicing factor RBM10 is frequently mutated in lung adenocarcinoma (LUAD), however its underlying molecular mechanism remains elusive. Here we identified RBM10 mutations in East Asian lung adenocarcinoma (LUAD) patients as the cancer driver, and compared them with those in Western LUAD patients in The Cancer Genome Atlas (TCGA). The majority of RBM10 mutations are loss-of-function mutations in LUAD patients from both populations. Furthermore, we found that silencing of RBM10 suppresses the proliferation and survival of LUAD cells, as well as the progression of exnograft tumor. To gain additional molecular insights, we conducted RNA-Seq experiments in lung epithelial cells with RBM10 knockdown and LUAD cells with overexpressed RBM10, as well as LUAD tissues with wild type or mutated RBM10 (with matched adjacent non-tumor tissues). We found that RBM10 exerts suppressive functions in LUAD by regulating splicing of many key genes involved in gene transcription and RNA processing. In addition, several RBM10-regulated RNA splicing events in LUADs are significantly associated with patient survival.
To further investigate the relationship between cancer and alternative splicing, we also analyzed other types of cancers and using the technology of the third generation sequencing to track down more cancer-related isoforms, which can significantly contribute to revealing cancer mechanisms.

 

Speaker2: Xuan Cao

 

Title: Dissecting the 3D chromatin architecture change during transcription factor-induced hepatic lineage conversion

 

Abstract: Chromatin architecture plays an critical role in regulation of transcription, yet its role in controlling cell fate remains largely unknown. During cell reprogramming, higher-order chromatin structure is subject to dynamic changes at different levels including compartments, TADs as well as chromatin loops. However, it remains elusive how key transcription factors regulate chromatin reorganization during cell reprogramming. In this study, we investigate the dynamic of chromatin architecture and its regulatory roles in cell fate conversion by integrative ananlysis of Hi-C data with gene expression, TF binding , histone modifications and chromatin accessibility. We identify ~1200 Compartment Switched Regions (CSRs) that show continuous  change at compartment level during cell fate conversion and these regions are functional enriched with lineage specific genes. Further, we find that the binding pattern of key transcription factor Foxa3 and chromatin accessibility in early stage of reprogramming can pre-determine the potential of compartment change to hepatocyte direction. CSRs are driven by Foxa3 binding and regulate lineage specific genes expression, effectively erasing the fibroblast-cell-specific chromatin structures while establishing hepatocyte-like 3D chromatin structures. The extension of CSR regions is restricted by loop anchors that served as an functional CSRs insulator. Additionally, CTCF binding regulates the establishment of hepatocyte-specific loops and the dissolvement of fibroblast-specific loops near cell identity genes. Together, our results show Foxa3 binding is the driving force to orchestrate chromatin architecture change during hepatic lineage conversion.