Genome-wide Identification of Post-translational Modulators of Transcription Factor Activity in Human B-Cells

The ability of a transcription factor to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms, resulting in highly context-dependent regulatory networks. However, high-throughput methods for the identification of proteins that affect transcription factor activity are still largely unavailable. Here we introduce a systems biology framework, MINDy (Modulator Inference by Network Dynamics), for the genome-wide identification of post-translational modulators of transcription factor activity within a specific cellular context. When used to dissect the regulation of MYC activity in human B lymphocytes, the approach inferred novel modulators of MYC function, which act by distinct mechanisms, including protein turn-over, transcriptional complex formation, and selective enzyme recruitment. MINDy is generally applicable to study the post-translational modulation of mammalian transcription factors in any cellular context. As such it provides a useful resource to dissect context-specific signaling pathways and combinatorial transcriptional regulation.