Feedforward regulation of <i>Myc</i> coordinates lineage-specific with housekeeping gene expression during B cell progenitor cell differentiation

by Isabel Ferreirós-Vidal, Thomas Carroll, Tianyi Zhang, Vincenzo Lagani, Ricardo N. Ramirez, Elizabeth Ing-Simmons, Alicia Garcia, Lee Cooper, Ziwei Liang, Georgios Papoutsoglou, Gopuraja Dharmalingam, Ya Guo, Sonia Tarazona, Sunjay J. Fernandes, Peri Noori, Gilad Silberberg, Amanda G. Fisher, Ioannis Tsamardinos, Ali Mortazavi, Boris Lenhard, Ana Conesa, Jesper Tegner, Matthias Merkenschlager, David Gomez-Cabrero

The differentiation of self-renewing progenitor cells requires not only the regulation of lineage- and developmental stage–specific genes but also the coordinated adaptation of housekeeping functions from a metabolically active, proliferative state toward quiescence. How metabolic and cell-cycle states are coordinated with the regulation of cell type–specific genes is an important question, because dissociation between differentiation, cell cycle, and metabolic states is a hallmark of cancer. Here, we use a model system to systematically identify key transcriptional regulators of Ikaros-dependent B cell–progenitor differentiation. We find that the coordinated regulation of housekeeping functions and tissue-specific gene expression requires a feedforward circuit whereby Ikaros down-regulates the expression of Myc. Our findings show how coordination between differentiation and housekeeping states can be achieved by interconnected regulators. Similar principles likely coordinate differentiation and housekeeping functions during progenitor cell differentiation in other cell lineages.

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