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Gene expression profile of right ventricles from adult wild type and Ezh2-deficient hearts

ABSTRACT: Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive marks during development that persist into adulthood, 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. 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. Four samples were analyzed. RNA was obtained from ventricles from two wild type and two Ezh2-deficient hearts.

ORGANISM(S): Mus musculus

SUBMITTER: Alex Williams

PROVIDER: E-GEOD-34274 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Project description:Adult-onset diseases can be associated with in utero events, but mechanisms for such temporally distant dysregulation of organ function remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive histone marks during development that persist into adulthood, but the function of Ezh2-mediated transcriptional stability in postnatal organ homeostasis is not understood. Here, we show that Ezh2 stabilizes the postnatal cardiac gene expression program and prevents cardiac pathology, primarily by repressing the homeodomain transcription factor Six1 in differentiating cardiac progenitors. Loss of Ezh2 in embryonic cardiac progenitors, but not in differentiated cardiomyocytes, resulted in postnatal cardiac pathology, including cardiomyocyte hypertrophy and fibrosis. Loss of Ezh2 caused broad derepression of skeletal muscle genes, including the homeodomain transcription factor Six1, which is expressed in cardiac progenitors but is normally silenced upon cardiac differentiation. Many of the deregulated genes are direct Six1 targets, implying a critical requirement for stable repression of Six1 in cardiac myocytes. Indeed, upon de-repression, Six1 promotes cardiac pathology, as it was sufficient to induce cardiac hypertrophy. Furthermore, genetic reduction of Six1 levels almost completely rescued the pathology of Ezh2-deficient hearts. Thus, repression of a single transcription factor in cardiac progenitors by Ezh2 is essential for stability of the adult heart gene expression program and homeostasis. Our results suggest that epigenetic dysregulation during discrete developmental windows can predispose to adult disease and dysregulated stress responses. Global gene expression profiles of Ezh2-deficient hearts. The right ventricle and the interventricular septum of five wild type (Ezh2f/f) and four Ezh2-deficient (Ezh2f/f;Mef2cAHF::Cre) mice were analyzed.

2011-12-31 | E-GEOD-30076 | biostudies-arrayexpress

Gene expression profile of right ventricles from adult wild type and Ezh2-deficient hearts

Project description:Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive marks during development that persist into adulthood, 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. 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.

2011-12-09 | GSE34274 | GEO

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

2011-12-31 | GSE30076 | GEO

RNA-Seq gene profiling of retinal ganglion cells in Math5Cre-driven Knockout of Ezh2 in mice at P0

2018-02-13 | GSE93674 | GEO

Next Generation Sequencing Analysis of Saccharopolyspora erytharea transcriptomes

Project description:We report the high-throughput profiling of saccharopolyspora erythraea life cycle in bioreactors. RNA was harvested at seven time-points from bioreactors, three points immediately before, one during and three following the metabolic switch (as evidenced by biomass cell dry weight). We prepared unstranded RNA libraries and sequenced 363 million reads for a total of 32.7Gb and a mean ~4,000 fold coverage of the genome. Our comprehensive sequencing showed the S.erythraea genome to be prevalently transcribed, with at least 85.8% of genome sequence from either strand being transcribed. We sequenced a bioreactor fermentation at seven time points.

2013-06-18 | E-GEOD-39722 | biostudies-arrayexpress

RNA-Seq and ChIP-Seq gene profiling of retinal ganglion cells in Math5Cre-driven Knockout of Ezh2 and G9a in murine retinal ganglion cells at P0

Project description:Epigenetic mark deposition during embryonic development contribute to postnatal homeostasis and tissue stability. Previously, we found out that Ezh2 contributes critically to the function and postnatal cell survival in bipolar cells but not in retinal ganglion cells in the retina. (Yan et al. Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1. Sci Report. doi:10.1038/srep33887; (Cheng L, Wong LJ, Yan N, Han RC et al. Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury. PLoS One 2018;13(2):e0191853.). In this study, we used RNA-seq to define up- and down regulated genes in both Ezh2 and G9a deficient (Math5Cre; Ezh2f/fG9af/+; dKO) retinal ganglion cells (RGC) to evaluate the hypothesis of Ezh2 and G9a interaction that has been discussed in other tissues but in the retina. ChIP-Seq was applied to evaluate H3K27me3 histone marks in retinal ganglion cells in wild type (WT), Ezh2 (Math5Cre; Ezh2-/-, sKO) and combined G9a-Ezh2 (Math5Cre; G9a+/-Ezh2-/-, dKO) knockout mutant mice at P1.

2022-07-26 | GSE136360 | GEO

Genome-wide profiling of E12.5 cardiomyocytes RNA expression in both heterozygous control and mutant

Project description:Congenital heart disease is among the most frequent major birth defects. Epigenetic marks are crucial for organogenesis, but their role in heart development is poorly understood. Polycomb Repressive Complex 2 (PRC2) trimethylates histone H3 at lysine 27, establishing H3K27me3 repressive epigenetic marks that promote tissue-specific differentiation by silencing ectopic gene programs. We studied the function of the catalytic subunit of PRC2, EZH2, in murine heart development. Early EZH2 inactivation by Nkx2-5Cre caused lethal congenital heart malformations, but slightly later EZH2 inactivation by cTNT-Cre did not. To study how the cardiomyocytes gene expression program is properly established in the early heart development, we combined the technologies of RNA sequencing and chromatin immunoprecipitation sequencing to identify the functional target genes directly repressed by EZH2. Intriguingly, these were enriched for transcriptional regulators of non-cardiac expression programs, such as transcription factors that regulate neuronal (Pax6) and cardiac progenitor genes (Isl1 and Six1). EZH2 was also required to maintain spatiotemporal regulation of cardiac gene expression, as Hcn4, Mlc2a, and Bmp10 were inappropriately upregulated in ventricular RNA. Furthermore, EZH2 was required for normal cardiomyocyte proliferation, establishing H3K27me3 epigenetic marks at cell cycle inhibitors Ink4a/b and repressing their expression. Our study reveals a previously undescribed role of EZH2 in regulating heart formation and shows that perturbation of the epigenetic landscape early cardiogenesis has sustained disruptive effects at later developmental stages. 8 E12.5 heart apex were used for RNA preparation each group.

2012-03-15 | E-GEOD-29992 | biostudies-arrayexpress

Six1 and Six2 of the sine oculis homeobox subfamily are not functionally interchangeable in mouse nephron formation

Project description:The vertebrate Six1 and Six2 arose by gene duplication from the Drosophila so (sine oculis) and have since diverged in their developmental expression patterns. Both genes are expressed in nephron progenitors of human fetal kidneys, and mutations in SIX1 or SIX2 cause branchio-oto-renal or renal hypodysplasia respectively. Since ~80% of SIX1 target sites are shared by SIX2, it is speculated that SIX1 and SIX2 may be functionally interchangeable by targeting common downstream genes. In contrast, in mouse kidneys, the expression of Six1 and Six2 only transiently overlaps in the metanephric mesenchyme before the onset of ureteric branching, and only Six2 expression is maintained in the nephron progenitors throughout development. This non-overlapping expression between Six1 and Six2 in mouse nephron progenitors promoted us to examine if Six1 can replace Six2. Surprisingly, forced expression of Six1 failed to rescue Six2-deficient kidney hypoplasia. We found that Six1 mediated Eya1 nuclear translocation and inhibited premature epithelialization of the progenitors but failed to rescue the proliferation defects and cell death caused by Six2-knockout. Genome-wide binding analyses showed that Six1 only bound to a small subset of Six2 target sites, but many Six2-bound loci that are crucial to the renewal and differentiation of nephron progenitors lacked Six1 occupancy. Thus, these data indicate that Six1 cannot substitute Six2 to drive nephrogenesis in mouse kidneys, demonstrating that these two transcription factors have not maintained equivalent biochemical properties since their divergence early in vertebrate evolution.

2022-01-27 | GSE189131 | GEO

Genome-wide profiling of E12.5 cardiomyocytes RNA expression in both heterozygous control and mutant

2012-03-15 | GSE29992 | GEO

Transcriptional profiling of human and mouse nephron progenitor cells

Project description:Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. In contrast, Six2 maintains later progenitor self-renewal from the onset of nephrogenesis. We compared Six2’s regulatory actions in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Further, RNA-seq and immunostaining revealed overlapping SIX1 and SIX2 progenitor activity in the 16 week human fetal kidney. Human SIX1 ChIP-seq revealed a similar set of targets to SIX2, and predicted both factors bind DNA through an identical recognition site. In contrast to the mouse where Six2 binds its own enhancers but doesn’t interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. In contrast, the mouse establishes only an auto-regulatory Six2 loop. It is tempting to speculate that differential SIX-factor regulation may contribute to species differences in the duration of progenitor programs and nephron output.

2016-01-31 | GSE73866 | GEO

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