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A core erythroid transcriptional network is repressed by a master regulator of myelo-lymphoid differentiation.

ABSTRACT: Two mechanisms that play important roles in cell fate decisions are control of a "core transcriptional network" and repression of alternative transcriptional programs by antagonizing transcription factors. Whether these two mechanisms operate together is not known. Here we report that GATA-1, SCL, and Klf1 form an erythroid core transcriptional network by co-occupying >300 genes. Importantly, we find that PU.1, a negative regulator of terminal erythroid differentiation, is a highly integrated component of this network. GATA-1, SCL, and Klf1 act to promote, whereas PU.1 represses expression of many of the core network genes. PU.1 also represses the genes encoding GATA-1, SCL, Klf1, and important GATA-1 cofactors. Conversely, in addition to repressing PU.1 expression, GATA-1 also binds to and represses >100 PU.1 myelo-lymphoid gene targets in erythroid progenitors. Mathematical modeling further supports that this dual mechanism of repressing both the opposing upstream activator and its downstream targets provides a synergistic, robust mechanism for lineage specification. Taken together, these results amalgamate two key developmental principles, namely, regulation of a core transcriptional network and repression of an alternative transcriptional program, thereby enhancing our understanding of the mechanisms that establish cellular identity.

SUBMITTER: Wontakal SN

PROVIDER: S-EPMC3309740 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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A core erythroid transcriptional network is repressed by a master regulator of myelo-lymphoid differentiation.

Wontakal Sandeep N SN Guo Xingyi X Smith Cameron C MacCarthy Thomas T Bresnick Emery H EH Bergman Aviv A Snyder Michael P MP Weissman Sherman M SM Zheng Deyou D Skoultchi Arthur I AI

Proceedings of the National Academy of Sciences of the United States of America 20120222 10

Two mechanisms that play important roles in cell fate decisions are control of a "core transcriptional network" and repression of alternative transcriptional programs by antagonizing transcription factors. Whether these two mechanisms operate together is not known. Here we report that GATA-1, SCL, and Klf1 form an erythroid core transcriptional network by co-occupying >300 genes. Importantly, we find that PU.1, a negative regulator of terminal erythroid differentiation, is a highly integrated co ...[more]

PMID: 22357756

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Dataset Information

A core erythroid transcriptional network is repressed by a master regulator of myelo-lymphoid differentiation.

Publications

A core erythroid transcriptional network is repressed by a master regulator of myelo-lymphoid differentiation.

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