The pioneering transcription factor C/EBPα coordinates cell fate and cell differentiation. The structure of C/EBPα comprises intrinsically disordered regions, multiple short linear motifs, and extensive post-translational side chain modifications (PTM), reflecting its modularity and functional plasticity. Here, we combined peptide matrix screening with biotin ligase proximity labeling proteomics to generate a PTM-dependent comprehensive protein interaction map of C/EBPα in myeloid cells. We found that protein interactions hotspots coincide with homologous conserved regions of the C/EBP family. PTMs alter the interaction spectrum of multi-valent C/EBP-motifs to configure a dynamic C/EBPα hub that selects co-regulatory components such as of the BAF/SWI-SNF complexes in an C/EBPα arginine-methylation and isoform state specific fashion. Our data suggest that the functional plasticity of C/EBPs is based on promiscuous interactions with protein machineries involved in gene regulation, epigenetics, genome organization, DNA replication, RNA processing and transport. The experimental strategy opens new avenues to systematically examine the PTM-dependent interactome of intrinsically disordered proteins as a basis to explore their multi-modal functions.