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A bivalent chromatin structure marks key developmental genes in embryonic stem cells, Cell 125
, 2006
"... The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by ex ..."
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The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed ‘‘bivalent domains,’ ’ consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
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, 2009
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www.elsevier.com/locate/ymcne
, 2005
"... In vivo transcriptional profile analysis reveals RNA splicing and ..."
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"... In this study gene regulation by MLL fusion proteins was investigated. Inducible cell lines using the estrogen receptor system were established that allowed for analysis of the early events after activation of an oncogene. A fusion of the MLL aminoterminus and the activation domain of Herpes simplex ..."
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In this study gene regulation by MLL fusion proteins was investigated. Inducible cell lines using the estrogen receptor system were established that allowed for analysis of the early events after activation of an oncogene. A fusion of the MLL aminoterminus and the activation domain of Herpes simplex VP16 was used to imitate leukemic MLL translocation events, the majority of which fuses the aminoterminal part of MLL to a transcriptional activator. It could be demonstrated that expression of biological targets of MLL and MLL fusion constructs increased following activation of the inducible protein MLL–VP16–ER–HA. The regulatory sequence of Hoxa9, expression of which is critically depending on MLL, was investigated in detail in order to understand the mechanism of MLL activation. Episomal reporter constructs were used to analyze the activation of different regions of the human Hoxa9 promoter by MLL–VP16–ER–HA. A fragment comprising nucleotides –118 / +46 was identified as sufficient for the response to induction of the fusion protein. Monoclonal antibodies were raised against MLL and used to monitor the recruitment of MLL–VP16–ER–HA to the episomal as well as to the chromosomal
Global Analysis of H3K4 Methylation Defines MLL Family Member Targets and Points to a Role for MLL1-Mediated H3K4
, 2009
"... A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccha-romyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 t ..."
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A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccha-romyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 to MLL4, are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1/ and Mll1/ mouse embryonic fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5 % of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs. Together these data provide insight into the redundancy and specialization
