Dataset Information

Modelling TERT regulation across 19 different cancer types based on the MIPRIP 2.0 gene regulatory network approach.

ABSTRACT: BACKGROUND:Reactivation of the telomerase reverse transcriptase gene TERT is a central feature for unlimited proliferation of the majority of cancers. However, the underlying regulatory processes are only partly understood. RESULTS:We assembled regulator binding information from serveral sources to construct a generic human and mouse gene regulatory network. Advancing our "Mixed Integer linear Programming based Regulatory Interaction Predictor" (MIPRIP) approach, we identified the most common and cancer-type specific regulators of TERT across 19 different human cancers. The results were validated by using the well-known TERT regulation by the ETS1 transcription factor in a subset of melanomas with mutations in the TERT promoter. Our improved MIPRIP2 R-package and the associated generic regulatory networks are freely available at https://github.com/KoenigLabNM/MIPRIP. CONCLUSION:MIPRIP 2.0 identified common as well as tumor type specific regulators of TERT. The software can be easily applied to transcriptome datasets to predict gene regulation for any gene and disease/condition under investigation.

SUBMITTER: Poos AM

PROVIDER: S-EPMC6937852 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Modelling TERT regulation across 19 different cancer types based on the MIPRIP 2.0 gene regulatory network approach.

Poos Alexandra M AM Kordaß Theresa T Kolte Amol A Ast Volker V Oswald Marcus M Rippe Karsten K König Rainer R

BMC bioinformatics 20191230 1

<h4>Background</h4>Reactivation of the telomerase reverse transcriptase gene TERT is a central feature for unlimited proliferation of the majority of cancers. However, the underlying regulatory processes are only partly understood.<h4>Results</h4>We assembled regulator binding information from serveral sources to construct a generic human and mouse gene regulatory network. Advancing our "Mixed Integer linear Programming based Regulatory Interaction Predictor" (MIPRIP) approach, we identified the ...[more]

PMID: 31888467

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Project description:The mechanisms generating stably differentiated cell-types from multipotent precursors are key to understanding normal development and have implications for treatment of cancer and the therapeutic use of stem cells. Pigment cells are a major derivative of neural crest stem cells and a key model cell-type for our understanding of the genetics of cell differentiation. Several factors driving melanocyte fate specification have been identified, including the transcription factor and master regulator of melanocyte development, Mitf, and Wnt signalling and the multipotency and fate specification factor, Sox10, which drive mitf expression. While these factors together drive multipotent neural crest cells to become specified melanoblasts, the mechanisms stabilising melanocyte differentiation remain unclear. Furthermore, there is controversy over whether Sox10 has an ongoing role in melanocyte differentiation. Here we use zebrafish to explore in vivo the gene regulatory network (GRN) underlying melanocyte specification and differentiation. We use an iterative process of mathematical modelling and experimental observation to explore methodically the core melanocyte GRN we have defined. We show that Sox10 is not required for ongoing differentiation and expression is downregulated in differentiating cells, in response to Mitfa and Hdac1. Unexpectedly, we find that Sox10 represses Mitf-dependent expression of melanocyte differentiation genes. Our systems biology approach allowed us to predict two novel features of the melanocyte GRN, which we then validate experimentally. Specifically, we show that maintenance of mitfa expression is Mitfa-dependent, and identify Sox9b as providing an Mitfa-independent input to melanocyte differentiation. Our data supports our previous suggestion that Sox10 only functions transiently in regulation of mitfa and cannot be responsible for long-term maintenance of mitfa expression; indeed, Sox10 is likely to slow melanocyte differentiation in the zebrafish embryo. More generally, this novel approach to understanding melanocyte differentiation provides a basis for systematic modelling of differentiation in this and other cell-types.

Dataset Information

Modelling TERT regulation across 19 different cancer types based on the MIPRIP 2.0 gene regulatory network approach.

Publications

Modelling TERT regulation across 19 different cancer types based on the MIPRIP 2.0 gene regulatory network approach.

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