Establishing a hematopoietic genetic network through locus-specific integration of chromatin regulators

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 36; pp. E3398 - E3407
• Main Authors: DeVilbiss, Andrew W, Boyer, Meghan E, Bresnick, Emery H
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03-09-2013; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Bioassays; Biological Sciences; Cell Line, Tumor; Cells, Cultured; Cellular biology; CHO Cells; Chromatin; Chromatin - genetics; Chromatin - metabolism; Cricetinae; Cricetulus; Erythrocytes; Erythroid Cells - metabolism; GATA1 Transcription Factor - genetics; GATA1 Transcription Factor - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Genetics; Hematopoietic Stem Cells - metabolism; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Mice; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oligonucleotide Array Sequence Analysis; PNAS Plus; Reverse Transcriptase Polymerase Chain Reaction; Ribozymes; RNA Interference; Transcription Factors - genetics; Transcription Factors - metabolism; erythroid; genomics; GATA; epigenetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1302771110

The establishment and maintenance of cell type-specific transcriptional programs require an ensemble of broadly expressed chromatin remodeling and modifying enzymes. Many questions remain unanswered regarding the contributions of these enzymes to specialized genetic networks that control critical processes, such as lineage commitment and cellular differentiation. We have been addressing this problem in the context of erythrocyte development driven by the transcription factor GATA-1 and its coregulator Friend of GATA-1 (FOG-1). As certain GATA-1 target genes have little to no FOG-1 requirement for expression, presumably additional coregulators can mediate GATA-1 function. Using a genetic complementation assay and RNA interference in GATA-1–null cells, we demonstrate a vital link between GATA-1 and the histone H4 lysine 20 methyltransferase PR-Set7/SetD8 (SetD8). GATA-1 selectively induced H4 monomethylated lysine 20 at repressed, but not activated, loci, and endogenous SetD8 mediated GATA-1–dependent repression of a cohort of its target genes. GATA-1 used different combinations of SetD8, FOG-1, and the FOG-1–interacting nucleosome remodeling and deacetylase complex component Mi2β to repress distinct target genes. Implicating SetD8 as a context-dependent GATA-1 corepressor expands the repertoire of coregulators mediating establishment/maintenance of the erythroid cell genetic network, and provides a biological framework for dissecting the cell type-specific functions of this important coregulator. We propose a coregulator matrix model in which distinct combinations of chromatin regulators are required at different GATA-1 target genes, and the unique attributes of the target loci mandate these combinations.