title: 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.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sandeep N
authors.initials: SN
authors.lastname: Wontakal
authors.forename: Xingyi
authors.initials: X
authors.lastname: Guo
authors.forename: Cameron
authors.initials: C
authors.lastname: Smith
authors.forename: Thomas
authors.initials: T
authors.lastname: MacCarthy
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
authors.forename: Aviv
authors.initials: A
authors.lastname: Bergman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.forename: Sherman M
authors.initials: SM
authors.lastname: Weissman
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Skoultchi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D004912:Erythrocytes; D050981:Erythroid-Specific DNA-Binding Factors / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008962:Models, Theoretical; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494689:Gata1 protein, mouse; C489366:Tal1 protein, mouse; C080774:erythroid Kruppel-like factor