Abstract
SummaryC/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.
Highlights
CCAAT enhancer binding protein alpha (C/EBPa) is a lineage instructing pioneering transcription factor involved in cell fate decisions in various cell types, including myeloid cells, adipocytes, hepatocytes, and skin cells
Unraveling C/ EBPa protein interaction networks is a prerequisite for understanding the multimodal functions of C/EBPa in hematopoiesis and leukemia
The myeloid C/EBPa interactome comprises promiscuous and post-translational modifications (PTM)-regulated interactions with protein machineries involved in gene expression, epigenetics, genome organization, DNA replication, RNA processing, and nuclear transport
Summary
CCAAT enhancer binding protein alpha (C/EBPa) is a lineage instructing pioneering transcription factor involved in cell fate decisions in various cell types, including myeloid cells, adipocytes, hepatocytes, and skin cells. C/EBPa cooperates with other transcription factors and chromatin modifying enzymes to regulate hematopoietic stem cell biology, lineage choice and expression of myeloid genes (Avellino and Delwel, 2017; Zaret and Carroll, 2011). Knockout experiments in mice show that C/EBPa regulates hematopoietic stem cell functions and that its removal blocks progenitor differentiation at the myeloid commitment stage (Bereshchenko et al, 2009; Kirstetter et al, 2008a; Zhang et al, 2004). The intronless CEBPA gene is mutated in approximately 10-15% of human acute myeloid leukemia (AML) cases. Experimental hematology and targeted mouse genetics have demonstrated that p30 C/EBPa represents a highly penetrant AML driver oncoprotein (Bereshchenko et al, 2009; Kirstetter et al, 2008b)
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