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Deciphering transcriptional regulation of NF-kB target genes using integrative omics approaches

Project description

Dissecting the mechanism of NF-kB transcriptional activation

Transcription factors that fall into the nuclear factor-kB (NF-kB) family orchestrate the expression of key genes implicated in immune responses, proliferation and apoptosis. At the same time, emerging evidence indicates a role for NF-kB in cancer onset and progression. Therefore, to develop an anti-NF-kB treatment for cancer, one would need to selectively target NF-kB genes associated with malignant transformation. With this in mind, the EU-funded RegulatioNFkB project proposes to investigate the mechanism of NF-kB-mediated transcriptional activation by focusing on the promoter regions of NF-kB responsive genes. Researchers will use genome editing and mass spectrometry to identify transcription factors and other proteins that interact at the promoters of these genes.

Objective

NF-kB is a family of transcription factors that regulate expression of genes that are involved in various cellular processes such as apoptosis, proliferation and differentiation. The NF-kB pathway is implicated in the initiation and progression of cancer and cancer cell drug resistance. Unfortunately, global NF-kB inhibition is harmful to the immune system; therefore, inhibition of a subset of NF-kB target genes that are linked to malignant transformation would be more appropriate. Different NF-kB target genes display distinct transcription activation kinetics, indicating that the molecular mechanisms driving expression of NF-kB target genes are strikingly diverse. Thus, it is highly interesting to study the factors that are involved in transcriptional activation of individual NF-kB responsive genes, both from a fundamental and clinical perspective. Here, we will develop two innovative strategies based on CRISPR/Cas9 based genome targeting combined with mass spectrometry-based technology to isolate single NF-kB target gene promoters upon NF-kB pathway activation and identify their constituents. We will also apply a complementary approach, ATAC-sequencing, to identify transcription factors that are involved in activation of NF-kB responsive genes. Moreover, we will study the underlying mechanisms and characterize the function of proteins that interact with NF-kB responsive promoters. Finally, the described mechanisms discovered in cancer cell lines will be verified and validated in small intestinal organoids, a non-transformed cell model for homeostasis in the intestinal epithelium. This ambitious and multidisciplinary project will greatly benefit from my expert knowledge regarding the NF-kB pathway combined with the expertise of the host laboratory in mass spectrometry and genomics. The project is expected to have a major impact in the research area of gene expression regulation in general and molecular cancer research focusing on the NF-kB pathway in particular.

Coordinator

STICHTING RADBOUD UNIVERSITEIT
Net EU contribution
€ 187 572,48
Address
HOUTLAAN 4
6525 XZ Nijmegen
Netherlands

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Region
Oost-Nederland Gelderland Arnhem/Nijmegen
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 187 572,48