DC projects

Research project

Understanding the Effects of IKAROS mutations to Inborn Errors of Immunity

Rationale and Objectives

The IKZF1 gene, which encodes the IKAROS transcription factor, is a key player in B and T cell differentiation and development. Mutations in this gene are associated with primary immunodeficiencies, including common variable immunodeficiency (CVID), a condition characterized by recurrent infections and autoimmunity. However, most CVID cases lack associated mutations, hinting at the involvement of non-genetic mechanisms. Recent research by Ballestar’s group has underscored the role of epigenetic regulation, particularly DNA methylation dynamics, in the CVID onset of discordant monozygotic twins (Rodríguez-Ubreva et al. Nat Comms 2022).  These findings pose intriguing questions about the precise contribution of genes like IKZF1 in monogenic CVID patients. Notably, IKAROS has been found to interact with chromatin remodeling complexes such as the MTA2/NURD complex (Kim J et al. Immunity 1999), suggesting a potential interplay between IKZF1 mutations and epigenetics in CVID onset.

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1) Obtaining single-cell resolution chromatin accessibility and transcriptomic profiles from patients with CVID, both with and without IKZF1 mutations.

2) Profiling the DNA methylation, histone modifications, and transcription factor binding in different B and T cell compartments from patients with CVID, both with and without IKZF1 mutations.

3) Exploit CRISPR/Cas9 tools and state-of-the-art in vitro differentiation protocols to model the impact of dysregulated molecular events caused by IKAROS on normal lymphoid commitment.

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Expected results

1) To uncover unique chromatin and gene expression signatures of IKZF1-mutated CVID patients across multiple immune cells at single-cell resolution.

2) To characterize the molecular mechanisms underlying the altered immune cell population in IKZF1-mutated CVID patients.

3) To leverage a high-confidence panel of Ikaros-mediated dysregulated molecular events holding the potential to cause CVID phenotype.

Planned secondments

OSR (Di Micco) to receive training on standards for gene correction, m12-m15 (2 months). EMBL (Zaugg), to receive training on standards for multi-omic data analysis, m16-m17 (1 month). IRB (Geiger) to learn CRISPR screens, m18-m21 (2 months). Finally, DC8 will learn how to valorize their results in the unique genomic-computational industry environment provided by qGenomics, m24 (1 month).

PhD programme

PhD in Biomedicine, University of Barcelona (UB), Spain