title: The Lineage-Specific Transcription Factor PU.1 Prevents Polycomb-Mediated Heterochromatin Formation at Macrophage-Specific Genes.
abstract: Lineage-specific transcription factors (TFs) are important determinants of cellular identity, but their exact mode of action has remained unclear. Here we show using a macrophage differentiation system that the lineage-specific TF PU.1 keeps macrophage-specific genes accessible during differentiation by preventing Polycomb repressive complex 2 (PRC2) binding to transcriptional regulatory elements. We demonstrate that the distal enhancer of a gene becomes bound by PRC2 as cells differentiate in the absence of PU.1 binding and that the gene is wrapped into heterochromatin, which is characterized by increased nucleosome occupancy and H3K27 trimethylation. This renders the gene inaccessible to the transcriptional machinery and prevents induction of the gene in response to an external signal in mature cells. In contrast, if PU.1 is bound at the transcriptional regulatory region of a gene during differentiation, PRC2 is not recruited, nucleosome occupancy is kept low, and the gene can be induced in mature macrophages. Similar results were obtained at the enhancers of other macrophage-specific genes that fail to bind PU.1 as an estrogen receptor fusion (PUER) in this system. These results show that one role of PU.1 is to exclude PRC2 and to prevent heterochromatin formation at macrophage-specific genes.
authors.affiliation: Genetics Graduate Program, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Mohita
authors.initials: M
authors.lastname: Tagore
authors.affiliation: Genetics Graduate Program, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McAndrew
authors.affiliation: Genetics Graduate Program, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Gjidoda
authors.affiliation: Genetics Graduate Program, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA floer@msu.edu.
authors.forename: Monique
authors.initials: M
authors.lastname: Floer
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D006570:Heterochromatin / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis / Q000235:genetics; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D009707:Nucleosomes / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D006570:Heterochromatin; D006657:Histones; D053762:Interleukin-12 Subunit p40; D053582:Interleukin-1alpha; D008070:Lipopolysaccharides; D009707:Nucleosomes; D063151:Polycomb Repressive Complex 2; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1