TY - JOUR
T1 - A core erythroid transcriptional network is repressed by a master regulator of myelo-lymphoid differentiation
AU - Wontakal, Sandeep N.
AU - Guo, Xingyi
AU - Smith, Cameron
AU - MacCarthy, Thomas
AU - Bresnick, Emery H.
AU - Bergman, Aviv
AU - Snyder, Michael P.
AU - Weissman, Sherman M.
AU - Zheng, Deyou
AU - Skoultchi, Arthur I.
PY - 2012/3/6
Y1 - 2012/3/6
N2 - 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.
AB - 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.
KW - ChIP sequencing
KW - Cross antagonism
KW - Erythropoiesis
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U2 - 10.1073/pnas.1121019109
DO - 10.1073/pnas.1121019109
M3 - Article
C2 - 22357756
AN - SCOPUS:84863264788
SN - 0027-8424
VL - 109
SP - 3832
EP - 3837
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -