Delineating a combined post-transcriptional and transcriptional gene regulatory network in T-cell development

• Applicant: Professor Dr. Andreas Krueger
• Subject Area: Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569302776

T cells are at the center of the adaptive immune response. They are formed in the thymus in an ordered process comprising phases of proliferation, somatic gene rearrangements and selection. The complete T-cell developmental process is governed by tight transcriptional and post-transcriptional control. Defective T-cell development may result in diseases, such as immunodeficiency, autoimmunity or leukemia. MicroRNAs are short non-coding RNAs that guide the RNA-induced silencing complex (RISC) to target mRNAs, resulting in repression through RNA degradation and/or translational inhibition. Our laboratory has made substantial contributions to characterizing miRNA-dependent control of T-cell development with a particular focus on miR-181. Despite the long time span since their discovery, which was recently recognized with the award of the 2024 Nobel Prize in Medicine and Physiology, key questions of miRNA function in physiologically relevant systems remain, such as: What are physiologically relevant targets of an individual miRNA in any given system? What are the underlying molecular features determining targeting hierarchies? What are the underlying molecular features determining the mechanism(s) of repression? Using a multi-omics approach, we have identified the biochemically validated targetome of miR-181 in murine thymocytes. We have discovered a novel subset of targets comprising KRAB-ZFP (Krüppel-associated box domain-containing zinc-finger protein) transcription factors as a putative co-targeting network. KRAB-ZFPs constitute the largest family of transcription factors in vertebrates and generally act as transcriptional repressors. Repression of KRAB-ZFPs was uniquely mediated by translational inhibition rather than mRNA degradation. This discovery allows us to address the questions of which and how individual KRAB-ZFP family members control T-cell development and to delineate the mechanisms how miRNA targeting discriminates between two alternative, yet non-mutually exclusive, modes of repression, mRNA degradation and translational inhibition. In conclusion, this project will broaden our mechanistic understanding of microRNA function in a physiologic context. In addition, it will establish how the interdependence of transcriptional and post-transcriptional gene regulators shapes T-cell development.

• DFG Programme: Research Grants