The Paf1 Complex Is Required for Histone H3 Methylation by COMPASS and Dot1p: Linking Transcriptional Elongation to Histone Methylation

ABSTRACT The Paf1 complex (Paf1C) interacts with RNA polymerase II (Pol II) and promotes histone methylation of transcribed coding sequences, but the mechanism of Paf1C recruitment is unknown. We show that Paf1C is not recruited directly by the activator Gcn4p but is dependent on preinitiation complex assembly and Ser5 carboxy-terminal domain phosphorylation for optimal association with ARG1 coding sequences. Importantly, Spt4p is required for Paf1C occupancy at ARG1 (and other genes) and for Paf1C association with Ser5-phosphorylated Pol II in cell extracts, whereas Spt4p-Pol II association is independent of Paf1C. Since spt4Δ does not reduce levels of Pol II at ARG1, Ser5 phosphorylation, or Paf1C expression, it appears that Spt4p (or its partner in DSIF, Spt5p) provides a platform on Pol II for recruiting Paf1C following Ser5 phosphorylation and promoter clearance. spt4Δ reduces trimethylation of Lys4 on histone H3, demonstrating a new role for yeast DSIF in promoting a Paf1C-dependent function in elongation.

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Early mammalian erythropoiesis requires the Dot1L methyltransferase

Blood ◽

10.1182/blood-2010-03-276501 ◽

2010 ◽

Vol 116 (22) ◽

pp. 4483-4491 ◽

Cited By ~ 89

Author(s):

Yi Feng ◽

Yanping Yang ◽

Manoela M. Ortega ◽

Jessica N. Copeland ◽

Mingcai Zhang ◽

...

Keyword(s):

Histone Methylation ◽

Histone H3 ◽

Mutant Mice ◽

Myeloid Differentiation ◽

Wild Type ◽

Erythroid Progenitors ◽

Small Vessels ◽

Histone H3 Methylation ◽

Important Regulator ◽

Steady State Levels

Histone methylation is an important regulator of gene expression; its coordinated activity is critical in complex developmental processes such as hematopoiesis. Disruptor of telomere silencing 1-like (DOT1L) is a unique histone methyltransferase that specifically methylates histone H3 at lysine 79. We analyzed Dot1L-mutant mice to determine influence of this enzyme on embryonic hematopoiesis. Mutant mice developed more slowly than wild-type embryos and died between embryonic days 10.5 and 13.5, displaying a striking anemia, especially apparent in small vessels of the yolk sac. Further, a severe, selective defect in erythroid, but not myeloid, differentiation was observed. Erythroid progenitors failed to develop normally, showing retarded progression through the cell cycle, accumulation during G0/G1 stage, and marked increase in apoptosis in response to erythroid growth factors. GATA2, a factor essential for early erythropoiesis, was significantly reduced in Dot1L-deficient cells, whereas expression of PU.1, a transcription factor that inhibits erythropoiesis and promotes myelopoiesis, was increased. These data suggest a model whereby DOT1L-dependent lysine 79 of histone H3 methylation serves as a critical regulator of a differentiation switch during early hematopoiesis, regulating steady-state levels of GATA2 and PU.1 transcription, thus controlling numbers of circulating erythroid and myeloid cells.

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Mapping Global Histone Methylation Patterns in the Coding Regions of Human Genes

Molecular and Cellular Biology ◽

10.1128/mcb.25.11.4650-4661.2005 ◽

2005 ◽

Vol 25 (11) ◽

pp. 4650-4661 ◽

Cited By ~ 81

Author(s):

Feng Miao ◽

Rama Natarajan

Keyword(s):

Histone Methylation ◽

Histone H3 ◽

Distribution Patterns ◽

Poor Correlation ◽

Histone Marks ◽

Coding Regions ◽

New Information ◽

Human Genes ◽

Histone H3 Methylation ◽

Methylation Patterns

ABSTRACT Histone methylation patterns in the human genome, especially in euchromatin regions, have not been systematically characterized. In this study, we examined the profile of histone H3 methylation (Me) patterns at different lysines (Ks) in the coding regions of human genes by genome-wide location analyses by using chromatin immunoprecipitation linked to cDNA arrays. Specifically, we compared H3-KMe marks known to be associated with active gene expression, namely, H3-K4Me, H3-K36Me, and H3-K79Me, as well as those associated with gene repression, namely, H3-K9Me, H3-K27Me, and H4-K20Me. We further compared these to histone lysine acetylation (H3-K9/14Ac). Our results demonstrated that: first, close correlations are present between active histone marks except between H3-K36Me2 and H3-K4Me2. Notably, histone H3-K79Me2 is closely associated with H3-K4Me2 and H3-K36Me2 in the coding regions. Second, close correlations are present between histone marks associated with gene silencing such as H3-K9Me3, H3-K27Me2, and H4-K20Me2. Third, a poor correlation is observed between euchromatin marks (H3-K9/K14Ac, H3-K4Me2, H3-K36Me2, and H3-K79Me2) and heterochromatin marks (H3-K9Me2, H3-K9Me3, H3-K27Me2, and H4-K20Me2). Fourth, H3-K9Me2 is neither associated with active nor repressive histone methylations. Finally, histone H3-K4Me2, H3-K4Me3, H3-K36Me2, and H3-K79Me2 are associated with hyperacetylation and active genes, whereas H3-K9Me2, H3-K9Me3, H3-K27Me2, and H4-K20Me2 are associated with hypoacetylation. These data provide novel new information regarding histone KMe distribution patterns in the coding regions of human genes.

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Caught in conspiracy: cooperation between DNA methylation and histone H3K9 methylation in the establishment and maintenance of heterochromatin

Biochemistry and Cell Biology ◽

10.1139/o05-043 ◽

2005 ◽

Vol 83 (3) ◽

pp. 385-395 ◽

Cited By ~ 38

Author(s):

Irina Stancheva

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Rna Interference ◽

Histone Methylation ◽

Functional Relationship ◽

Histone H3 ◽

H3k9 Methylation ◽

Complex Interactions ◽

Histone H3 Methylation ◽

Intensive Investigation

Heritable patterns of gene expression and gene silencing are determined by chromatin states that either permit or restrict transcription. Restrictive heterochromatin in most eukaryotes is characterized by high levels of DNA methylation and histone H3 methylation at lysine 9. The functional relationship between these two modifications is the focus of intensive investigation in various organisms from fungi to mammals. Complex interactions have been discovered among various components of DNA methylation and histone methylation pathways, proteins involved in the formation of higher-order chromatin structure, chromatin remodelling activities, and RNA interference. This review discusses some aspects of this crosstalk and the cooperation between DNA methylation and histone H3K9 methylation in the establishment and maintenance of heterochromatin.Key words: DNA methylation, H3K9 methylation, heterochromatin.

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