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

Sandeep N. Wontakal, Xingyi Guo, Cameron Smith, Thomas MacCarthy, Emery H. Bresnick, Aviv Bergman, Michael P. Snyder, Sherman M. Weissman, Deyou Zheng, Arthur I. Skoultchi

Research output: Contribution to journalArticle

43 Scopus citations

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. Herewe report that GATA-1, SCL, and Klf1 forman 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 ofmany 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.

Original languageEnglish (US)
Pages (from-to)3832-3837
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number10
DOIs
StatePublished - Mar 6 2012

Keywords

  • ChIP sequencing
  • Cross antagonism
  • Erythropoiesis

ASJC Scopus subject areas

  • General

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