Feedforward regulation of Myc coordinates lineage-specific with housekeeping gene expression during B cell progenitor cell differentiation.

Isabel Ferreirós-Vidal,Ziwei Liang,Ana Conesa,Amanda G Fisher,Tianyi Zhang,Ya Guo,Vincenzo Lagani,Matthias Merkenschlager,Peri Noori,Boris Lenhard,Lee Cooper,Gilad Silberberg,Gopuraja Dharmalingam,Elizabeth Ing-Simmons,David Gomez-Cabrero,Sonia Tarazona,Ioannis Tsamardinos,Ricardo N Ramírez ,Alícia G Gómez-Valadés ,Γεώργιος Παπουτσόγλου ,Jesper Tegnér ,A Mortazavi ,Sunjay Jude Fernandes ,Thomas Carroll

doi:10.1371/journal.pbio.2006506

Abstract

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.

Highlights

Cell proliferation, metabolic state, and differentiation are linked: proliferating progenitor cells exit the cell cycle and adjust their metabolism as they differentiate [1,2,3]
We find that the transition from proliferation to differentiation involves changes in the expression of genes, which can be categorized into cell-type–specific genes and broadly expressed “housekeeping” genes
The expression of many housekeeping genes is controlled by the gene regulatory factor Myc, whereas the expression of many B lymphocyte–specific genes is controlled by the Ikaros family of gene regulatory proteins

Summary

Introduction

Metabolic state, and differentiation are linked: proliferating progenitor cells exit the cell cycle and adjust their metabolism as they differentiate [1,2,3]. This coordination is thought to involve mutual antagonism between cyclin-dependent kinases that promote cell-cycle entry and transcription factors that induce tissue-specific gene expression [1,2]. We refer to quiescent, differentiating B cell progenitors as Fr.D following Hardy’s nomenclature [4]; this stage is known as the pre-B, pre-B2, or small pre–B cell stage (Fig 1A). IKZF1, the gene encoding Ikaros, is recurrently mutated in human B cell progenitor acute lymphoblastic leukemias (B-ALLs) with translocations between the IGH locus and the ABL1 proto-oncogene (BCR-ABL1) [16,17]

Methods

Results

Discussion

Conclusion