GFI1/HDAC1-axis differentially regulates immunosuppressive CD73 in human tumor-associated FOXP3+ Th17 and inflammation-linked Th17 cells.

Plasticity between Th17 and Treg cells is regarded as a crucial determinant of tumor-associated immunosuppression. Classically Th17 cells mediate inflammatory responses through production of cytokine IL17. Recently, Th17 cells have also been shown to acquire suppressive phenotypes in tumor microenvironment. However, the mechanism by which they acquire such immunosuppressive properties is still elusive. Here, we report that in tumor microenvironment Th17 cell acquires immunosuppressive properties by expressing Treg lineage-specific transcription factor FOXP3 and ectonucleotidase CD73. We designate this cell as Th17reg cell and perceive that such immunosuppressive property is dependent on CD73. It was observed that in classical Th17 cell, GFI1 recruits HDAC1 to change the euchromatin into tightly-packed heterochromatin at the proximal-promoter region of CD73 to repress its expression. Whereas in Th17reg cells GFI1 cannot get access to CD73-promoter due to heterochromatin state at its binding site and, thus, cannot recruit HDAC1, failing to suppress the expression of CD73.

PSCRIdb: A database of regulatory interactions and networks of pluripotent stem cell lines.

Pluripotency in stem cells is regulated by a complex network between the transcription factors, signaling molecules, mRNAs, and epigenetic regulators like non-coding RNAs. Different pluripotent stem cell (PSC) lines were isolated and characterized to study the regulatory network topology to understand the mechanism that control developmental potential of pluripotent cells. PSCRIdb is a manually curated database of regulatory interactions including protein-protein, protein-DNA, gene-gene, and miRNA-mRNA interactions in mouse and human pluripotent stem cells including embryonic stem cells and embryonic carcinoma cells. At present, 22 different mouse and human pluripotent stem-cell-line-specific regulatory interactions are compiled in the database. Detailed information of the four types of interaction data are presented in tabular format and graphical network view in Cytoscape layout. The database is available at http://bicresources.jcbose.ac.in/ ssaha4/pscridb. The database contains 3037 entries of experimentally validated molecular interactions that can be useful for systematic study of pluripotency integrating multi-omics data. In summary, the database can be a useful resource for identification of regulatory networks present in different pluripotent stem cell lines.

In silico modeling of phosphorylation dependent and independent c-Myc degradation.

BACKGROUND: c-Myc plays an important role in cell proliferation, cell growth and in differentiation, making it a key regulator for carcinogenesis and pluripotency. Tight control of c-myc turnover is required by ubiquitin-mediated degradation. This is achieved in the system by two F-box proteins Skp2 and FBXW7. RESULTS: Dynamic modelling technique was used to build two exclusive models for phosphorylation dependent degradation of Myc by FBXW7 (Model 1) and phosphorylation independent degradation by Skp2 (Model 2). Sensitivity analysis performed on these two models revealed that these models were corroborating experimental studies. It was also seen that Model 1 was more robust and perhaps more efficient in degrading c-Myc. These results questioned the existence of the two models in the system and to answer the question a combined model was hypothesised which had a decision making switch. The combined model had both Skp2 and FBXW7 mediated degradation where again the latter played a more important role. This model was able to achieve the lowest levels of ubiquitylated Myc and therefore functioned most efficiently in degradation of Myc. CONCLUSION: In this report, c-Myc degradation by two F-box proteins was mathematically evaluated based on the importance of c-Myc turnover. The study was performed in a homeostatic system and therefore, prompts the exploration of c-Myc degradation in cancer state and in pluripotent state.