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      Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis

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          Abstract

          Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown 1, 2 . The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive marks during development that persist into adulthood 39 , but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor Six1, which functions in cardiac progenitors but is stably silenced upon cardiac differentiation 10 . Ezh2 deletion in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable postnatal heart gene expression and homeostasis. Our results suggest that epigenetic dysregulation in embryonic progenitor cells predisposes to adult disease and dysregulated stress responses.

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          Most cited references21

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          EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency.

          Trimethylation on H3K27 (H3K27me3) mediated by Polycomb repressive complex 2 (PRC2) has been linked to embryonic stem cell (ESC) identity and pluripotency. EZH2, the catalytic subunit of PRC2, has been reported as the sole histone methyltransferase that methylates H3K27 and mediates transcriptional silencing. Analysis of Ezh2(-/-) ESCs suggests existence of an additional enzyme(s) catalyzing H3K27 methylation. We have identified EZH1, a homolog of EZH2 that is physically present in a noncanonical PRC2 complex, as an H3K27 methyltransferase in vivo and in vitro. EZH1 colocalizes with the H3K27me3 mark on chromatin and preferentially preserves this mark on development-related genes in Ezh2(-/-) ESCs. Depletion of Ezh1 in cells lacking Ezh2 abolishes residual methylation on H3K27 and derepresses H3K27me3 target genes, demonstrating a role of EZH1 in safeguarding ESC identity. Ezh1 partially complements Ezh2 in executing pluripotency during ESC differentiation, suggesting that cell-fate transitions require epigenetic specificity.
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            Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement.

            Polycomb group protein Ezh2 is an essential epigenetic regulator of embryonic development in mice, but its role in the adult organism is unknown. High expression of Ezh2 in developing murine lymphocytes suggests Ezh2 involvement in lymphopoiesis. Using Cre-mediated conditional mutagenesis, we demonstrated a critical role for Ezh2 in early B cell development and rearrangement of the immunoglobulin heavy chain gene (Igh). We also revealed Ezh2 as a key regulator of histone H3 methylation in early B cell progenitors. Our data suggest Ezh2-dependent histone H3 methylation as a novel regulatory mechanism controlling Igh rearrangement during early murine B cell development.
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              Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex.

              Multipotent progenitor cells of the cerebral cortex balance self-renewal and differentiation to produce complex neural lineages in a fixed temporal order in a cell-autonomous manner. We studied the role of the polycomb epigenetic system, a chromatin-based repressive mechanism, in controlling cortical progenitor cell self-renewal and differentiation. We found that the histone methyltransferase of polycomb repressive complex 2 (PCR2), enhancer of Zeste homolog 2 (Ezh2), is essential for controlling the rate at which development progresses within cortical progenitor cell lineages. Loss of function of Ezh2 removes the repressive mark of trimethylated histone H3 at lysine 27 (H3K27me3) in cortical progenitor cells and also prevents its establishment in postmitotic neurons. Removal of this repressive chromatin modification results in marked up-regulation in gene expression, the consequence of which is a shift in the balance between self-renewal and differentiation toward differentiation, both directly to neurons and indirectly via basal progenitor cell genesis. Although the temporal order of neurogenesis and gliogenesis are broadly conserved under these conditions, the timing of neurogenesis, the relative numbers of different cell types, and the switch to gliogenesis are all altered, narrowing the neurogenic period for progenitor cells and reducing their neuronal output. As a consequence, the timing of cortical development is altered significantly after loss of PRC2 function.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature Genetics
                1061-4036
                1546-1718
                12 December 2011
                22 January 2012
                01 September 2012
                : 44
                : 3
                : 343-347
                Affiliations
                [1 ]Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
                [2 ]Urological Diseases Research Center, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts, USA
                [3 ]Department of Pathology, Harvard Medical School, Boston, MA, USA
                [4 ]Harvard Stem Cell Institute, Cambridge, MA, USA
                [5 ]Department of Genetics, Harvard Medical School, Boston MA 02115 USA
                [6 ]Howard Hughes Medical Institute, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA
                [7 ]Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY, USA
                [8 ]Department of Pediatrics, Cardiovascular Research Institute. University of California, San Francisco, CA, USA
                [9 ]Institute for Regeneration Medicine, University of California, San Francisco, CA, USA
                Author notes
                Correspondence should be addressed to B.G.B. ( bbruneau@ 123456gladstone.ucsf.edu )
                Article
                nihpa343351
                10.1038/ng.1068
                3288669
                22267199
                026af84c-0094-476b-a76f-4fff743ac440

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                History
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: U01 HL098179-04 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: U01 HL098179-03 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: U01 HL098179-02 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: U01 HL098179-01 || HL
                Categories
                Article

                Genetics
                Genetics

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