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Lothar Hennighausen - One of the best experts on this subject based on the ideXlab platform.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and ezh2
PLOS Genetics, 2020Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, EZH1 and Ezh2. Here, we used EZH1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic EZH1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, EZH1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, EZH1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and ezh2
bioRxiv, 2019Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Summary Background Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous catalytic subunits EZH1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver. Results We used EZH1-knockout mice with a hepatocyte-specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic EZH1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were induced in EZH1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice to hepatotoxin-induced liver pathology. Conclusions EZH1/Ezh2-catalyzed H3K27-trimethyation is thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of the sex-bias in liver disease susceptibility.
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loss of ezh2 results in precocious mammary gland development and activation of stat5 dependent genes
Nucleic Acids Research, 2015Co-Authors: Kyung Hyun Yoo, Keunsoo Kang, Gertraud W Robinson, Tim Hensel, Lothar HennighausenAbstract:Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factors STAT5A and STAT5B (STAT5), which also regulate temporal activation of mammary signature genes. This study addressed the question whether the methyltransferase and transcriptional co-activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium during pregnancy and the activation of mammary-specific STAT5 target genes. This coincided with enhanced occupancy of these loci by STAT5, EZH1 and RNA Pol II. Limited activation of differentiation-specific genes was observed in mammary epithelium lacking both EZH2 and STAT5, suggesting a modulating but not mandatory role for STAT5. Loss of EZH2 did not result in overt changes in genome-wide and gene-specific H3K27me3 profiles, suggesting compensation through enhanced EZH1 recruitment. Differentiated mammary epithelia did not form in the combined absence of EZH1 and EZH2. Transplantation experiments failed to demonstrate a role for EZH2 in the activity of mammary stem and progenitor cells. In summary, while EZH1 and EZH2 serve redundant functions in the establishment of H3K27me3 marks and the formation of mammary alveoli, the presence of EZH2 is required to control progressive differentiation of milk secreting epithelium during pregnancy.
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The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.
Molecular carcinogenesis, 2014Co-Authors: Woo Kyun Bae, Kyung Hyun Yoo, Ji Shin Lee, Young Ho Kim, Ik-joo Chung, Min Ho Park, Jung Han Yoon, Priscilla A. Furth, Lothar HennighausenAbstract:Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.
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ezh2 methyltransferase and h3k27 methylation in breast cancer
International Journal of Biological Sciences, 2012Co-Authors: Kyung Hyun Yoo, Lothar HennighausenAbstract:Histone modifications are thought to control the regulation of genetic programs in normal physiology and cancer. Methylation (mono-, di-, and tri-methylation) on histone H3 lysine (K) 27 induces transcriptional repression, and thereby participates in controlling gene expression patterns. Enhancer of zeste (EZH) 2, a methyltransferase and component of the polycomb repressive complex 2 (PRC2), plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Abnormal EZH2 expression has been associated with various cancers including breast cancer. Here, we discuss the contribution of EZH2 and the PRC2 complex in controlling the H3K27 methylation status and subsequent consequences on genomic instability and the cell cycle in breast cancer cells. We also discuss distinct molecular mechanisms used by EZH2 to suppress BRCA1 functions.
Woo Kyun Bae - One of the best experts on this subject based on the ideXlab platform.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and ezh2
PLOS Genetics, 2020Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, EZH1 and Ezh2. Here, we used EZH1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic EZH1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, EZH1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, EZH1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and ezh2
bioRxiv, 2019Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Summary Background Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous catalytic subunits EZH1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver. Results We used EZH1-knockout mice with a hepatocyte-specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic EZH1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were induced in EZH1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice to hepatotoxin-induced liver pathology. Conclusions EZH1/Ezh2-catalyzed H3K27-trimethyation is thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of the sex-bias in liver disease susceptibility.
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The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.
Molecular carcinogenesis, 2014Co-Authors: Woo Kyun Bae, Kyung Hyun Yoo, Ji Shin Lee, Young Ho Kim, Ik-joo Chung, Min Ho Park, Jung Han Yoon, Priscilla A. Furth, Lothar HennighausenAbstract:Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.
Kenneth S Zaret - One of the best experts on this subject based on the ideXlab platform.
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prc2 proteins EZH1 and ezh2 regulate timing of postnatal hepatocyte maturation and fibrosis by repressing gene expression at promoter regions in euchromatin in mice
Gastroenterology, 2019Co-Authors: Jessica Mae Grindheim, Dario Nicetto, Greg Donahue, Kenneth S ZaretAbstract:Abstract Background & Aims Little is known about mechanisms of postnatal hepatocyte maturation or chromatin regulation of genes that control fibrogenesis. We investigated transcription of genes that regulate fibrosis and the effects of chromatin compaction and the polycomb repressive complex 2 (PRC2) in postnatal hepatocytes of mice, focusing on the roles of the histone methyltransferases EZH1 and EZH2. Methods Hepatocytes were isolated from C57BL/6J and C3H mice, as well as mice with liver-specific disruption of EZH1 and/or Ezh2 , at postnatal day 14 (P14) and 2 months after birth (M2). Liver tissues were collected and analyzed by RNA-seq, H3K27me3 chromatin immunoprecipitation-seq, and sonication-resistant heterochromatin-seq (a method to map heterochromatin) analyses. Liver damage was characterized by histologic analysis. Results We found more than 3000 genes differentially expressed in hepatocytes during P14 to M2 liver maturation. Disruption of EZH1 and Ezh2 in livers caused perinatal hepatocytes to differentiate prematurely and express genes at P14 that would normally be induced by M2. This resulted in liver fibrosis. Genes with H3K27me3-postive and H3K4me3-positive promoter regions in euchromatin were prematurely induced in hepatocytes with loss of EZH1 and EZH2—these genes included those that regulate hepatocyte maturation, fibrosis, and genes not specifically associated with the liver lineage. Conclusions The PRC2 proteins EZH1 and EZH2 regulate genes that control hepatocyte maturation and fibrogenesis and genes not specifically associated with the liver lineage by acting at promoter regions in euchromatin. EZH1 and EZH2 thereby promote liver homeostasis and prevent liver damage. Strategies to manipulate PRC2 proteins might be used to improve hepatocyte derivation protocols or developed for treatment of patients with liver fibrosis.
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polycomb repressive complex 2 proteins EZH1 and ezh2 regulate timing of postnatal hepatocyte maturation and fibrosis by repressing gene expression at promoter regions in euchromatin in mice
Gastroenterology, 2019Co-Authors: Jessica Mae Grindheim, Dario Nicetto, Greg Donahue, Kenneth S ZaretAbstract:Background & Aims Little is known about mechanisms of postnatal hepatocyte maturation or chromatin regulation of genes that control fibrogenesis. We investigated the transcription of genes that regulate fibrosis and the effects of chromatin compaction and the polycomb repressive complex 2 in postnatal hepatocytes of mice, focusing on the roles of the histone methyltransferases EZH1 and EZH2. Methods Hepatocytes were isolated from C57BL/6J and C3H mice, as well as mice with liver-specific disruption of EZH1 and/or Ezh2 , at postnatal day 14 and 2 months after birth. Liver tissues were collected and analyzed by RNA sequencing, H3K27me3 chromatin immunoprecipitation sequencing, and sonication-resistant heterochromatin sequencing (a method to map heterochromatin) analyses. Liver damage was characterized by histologic analysis. Results We found more than 3000 genes differentially expressed in hepatocytes during liver maturation from postnatal day 14 to month 2 after birth. Disruption of EZH1 and Ezh2 in livers caused perinatal hepatocytes to differentiate prematurely and express genes at postnatal day 14 that would normally be induced by month 2. This resulted in liver fibrosis. Genes with H3K27me3-postive and H3K4me3-positive promoter regions in euchromatin were prematurely induced in hepatocytes with loss of EZH1 and EZH2—these genes included those that regulate hepatocyte maturation, fibrosis, and genes not specifically associated with the liver lineage. Conclusions The polycomb repressive complex 2 proteins EZH1 and EZH2 regulate genes that control hepatocyte maturation and fibrogenesis and genes not specifically associated with the liver lineage by acting at promoter regions in euchromatin. EZH1 and EZH2 thereby promote liver homeostasis and prevent liver damage. Strategies to manipulate polycomb repressive complex 2 proteins might be used to improve hepatocyte derivation protocols or developed for treatment of patients with liver fibrosis.
Scott W Lowe - One of the best experts on this subject based on the ideXlab platform.
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the polycomb complex prc2 supports aberrant self renewal in a mouse model of mll af9 nras g12d acute myeloid leukemia
Oncogene, 2013Co-Authors: Junwei Shi, Eric Wang, Johannes Zuber, Amy R Rappaport, Meredith J Taylor, Christopher Johns, Scott W LoweAbstract:The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein mixed lineage leukemia (MLL) can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that requires multiple epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or EZH1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer.
Linda Sperling - One of the best experts on this subject based on the ideXlab platform.
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The Polycomb protein Ezl1 mediates H3K9 and H3K27 methylation to repress transposable elements in Paramecium
Nature Communications, 2019Co-Authors: Andrea Frapporti, Caridad Miró Pina, Olivier Arnaiz, Daniel Holoch, Takayuki Kawaguchi, Adeline Humbert, Evangelia Eleftheriou, Bérangère Lombard, Damarys Loew, Linda SperlingAbstract:In animals and plants, the H3K9me3 and H3K27me3 chromatin silencing marks are deposited by different protein machineries. H3K9me3 is catalyzed by the SET-domain SU(VAR)3-9 enzymes, while H3K27me3 is catalyzed by the SET-domain Enhancer-of-zeste enzymes, which are the catalytic subunits of Polycomb Repressive Complex 2 (PRC2). Here, we show that the Enhancer-of-zeste-like protein Ezl1 from the unicellular eukaryote Paramecium tetraurelia, which exhibits significant sequence and structural similarities with human EZH2, catalyzes methylation of histone H3 in vitro and in vivo with an apparent specificity toward K9 and K27. We find that H3K9me3 and H3K27me3 co-occur at multiple families of transposable elements in an Ezl1-dependent manner. We demonstrate that loss of these histone marks results in global transcriptional hyperactivation of transposable elements with modest effects on protein-coding gene expression. Our study suggests that although often considered functionally distinct, H3K9me3 and H3K27me3 may share a common evolutionary history as well as a common ancestral role in silencing transposable elements.
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Identification and functional analysis of EZL genes.
2014Co-Authors: Maoussi Lhuillier-akakpo, Andrea Frapporti, Linda Sperling, Cyril Denby Wilkes, Mélody Matelot, Michel Vervoort, Sandra DuharcourtAbstract:A. Phylogenetic analysis of the EZH/EZL SET domain proteins. The part of the Maximum-likelihood (ML) tree shown in Figure S5 and which includes the EZH/EZL proteins, is depicted. Statistical supports (aLRT values) are indicated on the nodes by colored circles (color code is indicated in the figure). Species abbreviations: Amac = Allomyces macrogynus (Fungi); Atha = Arabidopsis thaliana (Virdiplantae); Aque = Amphimedon queenslandica (Metazoa); Bflo = Branchiostoma floridae (Metazoa); Dmel = Drosophila melanogaster (Metazoa); Hsap = Homo sapiens (Metazoa); Mbre = Monosiga brevicolis (choanoflagellata); Nvec = Nematostella (Metazoa); Ptet = Paramecium tetraurelia (Ciliata); Spun = Spizellomyces punctatus (Fungi); Tthe = Tetrahymena thermophila (Ciliata); Ttra = Thecamonas trahens (Apusozoa). B. Expression patterns of EZL genes during the life cycle. EZL, DCL2, DCL3, DCL5 and PGM gene expression levels, as determined by microarray expression data during autogamy time-course experiments [26]. The vegetative time point (V) consists of 4 samples from mass cultures containing only log-phase cells showing no sign of meiosis. The meiosis time point (M) consists of 4 samples containing 20-39% of cells undergoing meiosis, and little or no fragmentation of the maternal MAC. The fragmentation (F) time point consists of 4 samples that contained a similar proportion of meiotic cells (20-29%) as the M time point, but also contained 37-43% of cells with a fragmented maternal MAC. The D1 time point groups 3 samples with 35-56% of cells with fragmented maternal MACs and 35-51% of cells that already contained clearly visible new MACs. D2 consists of 3 samples with 73-98% of cells with visible new MACs, and the D3 samples were taken ∼10 hours after the D2 samples. C. Detection of EZL and PGM mRNA during autogamy by RT-PCR. Total RNAs were extracted at each time point (see Fig. S7), were reverse transcribed and cDNAs were amplified by PCR with gene specific primers and, as a loading control, with primers for the T1b gene, which encodes a component of the secretory granules [55]. D. PCR detection of IES 51A4578 circles with divergent primers on genomic DNA at each time point shown in Figure S7 after ICL7 (control) or EZL1 silencing. E. Lethality of post-autogamous progeny following EZL gene silencing. The gene targeted in each silencing experiment is indicated. Two non-overlapping fragments (#1 and #2) of EZL1 gene were used independently. The ND7 or ICL7 genes were used as control (CTL) RNAi targets, since their silencing has no effect on sexual processes [27]. Autogamy was also performed in standard K. pneumoniae medium (none). Cells were starved in each medium to induce autogamy and, following 3-4 days of starvation, autogamous cells were transferred individually to K. pneumoniae medium to monitor growth of sexual progeny. The total number of autogamous cells analyzed for each RNAi and the number of independent experiments (in parenthesis) are indicated. Death in progeny after EZL1 silencing was observed after less than three cell divisions. The absence of lethality observed after EZL2, EZL3a, EZL3b, EZL4 KDs should be taken with caution as the level of KDs was not measured.
