Abstract
EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Bone Marrow Cells / cytology
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Bone Marrow Cells / immunology
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CD11b Antigen / genetics
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CD11b Antigen / immunology
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Cell Cycle / drug effects
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Cell Cycle / genetics*
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Cell Cycle / immunology
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Cell Differentiation
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Cell Lineage / drug effects
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Cell Lineage / genetics*
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Cell Lineage / immunology
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Epigenesis, Genetic / immunology
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Interleukin-12 / pharmacology
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Killer Cells, Natural / cytology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Promoter Regions, Genetic
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Protein Binding
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Spleen / cytology
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Spleen / immunology
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T-Box Domain Proteins / deficiency
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T-Box Domain Proteins / genetics*
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T-Box Domain Proteins / immunology
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Transcription, Genetic
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
Substances
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CD11b Antigen
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Eomes protein, mouse
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Itgam protein, mouse
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Interleukin-12