PRISMA and BioID disclose a motifs-based interactome of the intrinsically disordered transcription factor C/EBPα

Evelyn Ramberger; Valeria Sapozhnikova; Elisabeth Kowenz-Leutz; Karin Zimmermann; Nathalie Nicot; Petr V Nazarov; Daniel Perez-Hernandez; Ulf Reimer; Philipp Mertins; Gunnar Dittmar; Achim Leutz

doi:10.1016/j.isci.2021.102686

PRISMA and BioID disclose a motifs-based interactome of the intrinsically disordered transcription factor C/EBPα

iScience. 2021 Jun 4;24(6):102686. doi: 10.1016/j.isci.2021.102686. eCollection 2021 Jun 25.

Authors

Affiliations

¹ Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
² Quantitative Biology Unit, Luxembourg Institute of Health, 1a Rue Thomas Edison, 1445 Strassen, Luxembourg.
³ JPT Peptide Technologies GmbH, Volmerstrasse 5, 12489 Berlin, Germany.
⁴ Institute of Biology, Humboldt University of Berlin, 10115 Berlin, Germany.

Abstract

C/EBPα represents a paradigm intrinsically disordered transcription factor containing short linear motifs and post-translational modifications (PTM). Unraveling C/EBPα protein interaction networks is a prerequisite for understanding the multi-modal functions of C/EBPα in hematopoiesis and leukemia. Here, we combined arrayed peptide matrix screening (PRISMA) with BioID to generate an in vivo validated and isoform specific interaction map of C/EBPα. The myeloid C/EBPα interactome comprises promiscuous and PTM-regulated interactions with protein machineries involved in gene expression, epigenetics, genome organization, DNA replication, RNA processing, and nuclear transport. C/EBPα interaction hotspots coincide with homologous conserved regions of the C/EBP family that also score as molecular recognition features. PTMs alter the interaction spectrum of C/EBP-motifs to configure a multi-valent transcription factor hub that interacts with multiple co-regulatory components, including BAF/SWI-SNF or Mediator complexes. Combining PRISMA and BioID is a powerful strategy to systematically explore the PTM-regulated interactomes of intrinsically disordered transcription factors.

Keywords: Omics; Proteomics; Transcriptomics.