H3 K79 dimethylation marks developmental activation of the β-globin gene but is reduced upon LCR-mediated high-level transcription

Abstract Genome-wide analyses of the relationship between H3 K79 dimethylation and transcription have revealed contradictory results. To clarify this relationship at a single locus, we analyzed expression and H3 K79 modification levels of wild-type (WT) and transcriptionally impaired β-globin mutant genes during erythroid differentiation. Analysis of fractionated erythroid cells derived from WT/Δ locus control region (LCR) heterozygous mice reveals no significant H3 K79 dimethylation of the β-globin gene on either allele prior to activation of transcription. Upon transcriptional activation, H3 K79 di-methylation is observed along both WT and ΔLCR alleles, and both alleles are located in proximity to H3 K79 dimethylation nuclear foci. However, H3 K79 di-methylation is significantly increased along the ΔLCR allele compared with the WT allele. In addition, analysis of a partial LCR deletion mutant reveals that H3 K79 dimethylation is inversely correlated with β-globin gene expression levels. Thus, while our results support a link between H3 K79 dimethylation and gene expression, high levels of this mark are not essential for high level β-globin gene transcription. We propose that H3 K79 dimethylation is destabilized on a highly transcribed template.

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SATB1 family protein expressed during early erythroid differentiation modifies globin gene expression

Blood ◽

10.1182/blood-2004-08-2988 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3330-3339 ◽

Cited By ~ 65

Author(s):

Jie Wen ◽

Suming Huang ◽

Heather Rogers ◽

Liliane A. Dickinson ◽

Terumi Kohwi-Shigematsu ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Activation ◽

Binding Protein ◽

Globin Gene ◽

K562 Cells ◽

Erythroid Differentiation ◽

Erythroid Progenitor ◽

Family Protein ◽

Globin Promoter ◽

Globin Gene Expression

AbstractSpecial AT-rich binding protein 1 (SATB1) nuclear protein, expressed predominantly in T cells, regulates genes through targeting chromatin remodeling during T-cell maturation. Here we show SATB1 family protein induction during early human adult erythroid progenitor cell differentiation concomitant with ϵ-globin expression. Erythroid differentiation of human erythroleukemia K562 cells by hemin simultaneously increases γ-globin and down-regulates SATB1 family protein and ϵ-globin gene expression. Chromatin immunoprecipitation using anti-SATB1 anti-body shows selective binding in vivo in the β-globin cluster to the hypersensitive site 2 (HS2) in the locus control region (LCR) and to the ϵ-globin promoter. SATB1 overexpression increases ϵ-globin and decreases γ-globin gene expression accompanied by histone hyperacetylation and hypomethylation in chromatin from the ϵ-globin promoter and HS2, and histone hypoacetylation and hypermethylation associated with the γ-globin promoter. In K562 cells SATB1 family protein forms a complex with CREB-binding protein (CBP) important in transcriptional activation. In cotransfection experiments, increase in ϵ-promoter activity by SATB1 was amplified by CBP and blocked by E1A, a CBP inhibitor. Our results suggest that SATB1 can up-regulate the ϵ-globin gene by interaction with specific sites in the β-globin cluster and imply that SATB1 family protein expressed in the erythroid progenitor cells may have a role in globin gene expression during early erythroid differentiation. (Blood. 2005;105:3330-3339)

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DNA Methylation and Globin Gene Expression.

Blood ◽

10.1182/blood.v112.11.sci-19.sci-19 ◽

2008 ◽

Vol 112 (11) ◽

pp. sci-19-sci-19

Author(s):

Yogenthiran Saunthararajah ◽

Donald Lavelle

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Sickle Cell Disease ◽

Globin Gene ◽

Histone H3 ◽

Erythroid Differentiation ◽

Cell Disease ◽

High Level ◽

Globin Gene Expression

Understanding how the human γ-globin gene is regulated has important clinical implications because increased levels of fetal hemoglobin (HbF) are beneficial to patients with sickle cell disease and β-thalassemia. DNA methylation is strongly implicated in developmental silencing of the γ-globin gene based on: an inverse correlation between DNA methylation of the γ-globin gene and its expression, the acquisition of CpG residues within the γ-globin 5’ region during evolution as the γ-globin gene was recruited to fetal stage expression, and the ability of pharmacological inhibitors of DNA methyltransferase (5-azacytidine; decitabine) to reactivate high-level expression of the γ-globin gene in experimental primates that led to clinical trials demonstrating that decitabine increased HbF to therapeutic levels in patients with sickle cell disease. Decitabine treatment in vivo decreases DNA methylation of the γ-globin gene and increases association of RNA polymerase II, acetyl Histone H3 and H4, and Histone H3 (lys4) trimethyl with the γ-globin gene, strongly suggesting that decitabine increases γ-globin gene transcription. These results are consistent with the hypothesis that γ-globin expression in adults is repressed by the binding of methyl DNA binding proteins to the methylated γ-globin promoter with subsequent recruitment of co-repressor complexes that actively repress γ-globin transcription. The reduction of γ-globin gene DNA methylation induced pharmacologically in adults by decitabine is linked to high level γ-globin expression, as is the complete loss of γ-globin gene methylation attained physiologically during erythroid differentiation of fetal liver hematopoietic progenitor cells. The mechanism of action of the drug has not been definitively established, however, and the role of DNA methylation in regulation of γ-globin gene expression remains an active area of investigation. High level γ-globin expression in baboon erythroid progenitor cell cultures without a reduction of γ-globin gene DNA methylation suggests the existence of alternative mechanisms of activation. In addition to reducing DNA methylation, decitabine activates the p38 MAP kinase pathway, increases p21WAF, and accelerates terminal erythroid differentiation. The role of these effects remains to be investigated. Increased understanding of the role of DNA methylation in γ-globin gene regulation is likely to impact the design of future therapies to increase HbF levels.

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Genome-Wide Expression and Alternative Splicing in Domesticated Sunflowers (Helianthus annuus L.) under Flooding Stress

Agronomy ◽

10.3390/agronomy11010092 ◽

2021 ◽

Vol 11 (1) ◽

pp. 92

Author(s):

Joon Seon Lee ◽

Lexuan Gao ◽

Laura Melissa Guzman ◽

Loren H. Rieseberg

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Mixed Model ◽

Agricultural Land ◽

Alcohol Fermentation ◽

Expression Levels ◽

Flooding Stress ◽

Genome Wide ◽

And Control ◽

Gene Expression Levels

Approximately 10% of agricultural land is subject to periodic flooding, which reduces the growth, survivorship, and yield of most crops, reinforcing the need to understand and enhance flooding resistance in our crops. Here, we generated RNA-Seq data from leaf and root tissue of domesticated sunflower to explore differences in gene expression and alternative splicing (AS) between a resistant and susceptible cultivar under both flooding and control conditions and at three time points. Using a combination of mixed model and gene co-expression analyses, we were able to separate general responses of sunflower to flooding stress from those that contribute to the greater tolerance of the resistant line. Both cultivars responded to flooding stress by upregulating expression levels of known submergence responsive genes, such as alcohol dehydrogenases, and slowing metabolism-related activities. Differential AS reinforced expression differences, with reduced AS frequencies typically observed for genes with upregulated expression. Significant differences were found between the genotypes, including earlier and stronger upregulation of the alcohol fermentation pathway and a more rapid return to pre-flooding gene expression levels in the resistant genotype. Our results show how changes in the timing of gene expression following both the induction of flooding and release from flooding stress contribute to increased flooding tolerance.

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Intra- and inter-specific variations of gene expression levels in yeast are largely neutral

10.1101/089995 ◽

2016 ◽

Cited By ~ 1

Author(s):

Jian-Rong Yang ◽

Calum Maclean ◽

Chungoo Park ◽

Huabin Zhao ◽

Jianzhi Zhang

Keyword(s):

Gene Expression ◽

Genome Sequence ◽

Large Fraction ◽

General Role ◽

Expression Levels ◽

Genome Wide ◽

Sequence Variations ◽

Expression Evolution ◽

Molecular Phenotypes ◽

Gene Expression Levels

ABSTRACTIt is commonly, although not universally, accepted that most intra- and inter-specific genome sequence variations are more or less neutral, whereas a large fraction of organism-level phenotypic variations are adaptive. Gene expression levels are molecular phenotypes that bridge the gap between genotypes and corresponding organism-level phenotypes. Yet, it is unknown whether natural variations in gene expression levels are mostly neutral or adaptive. Here we address this fundamental question by genome-wide profiling and comparison of gene expression levels in nine yeast strains belonging to three closely related Saccharomyces species and originating from five different ecological environments. We find that the transcriptome-based clustering of the nine strains approximates the genome sequence-based phylogeny irrespective of their ecological environments. Remarkably, only ∼0.5% of genes exhibit similar expression levels among strains from a common ecological environment, no greater than that among strains with comparable phylogenetic relationships but different environments. These and other observations strongly suggest that most intra- and inter-specific variations in yeast gene expression levels result from the accumulation of random mutations rather than environmental adaptations. This finding has profound implications for understanding the driving force of gene expression evolution, genetic basis of phenotypic adaptation, and general role of stochasticity in evolution.

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Histone H3K9 methylation promotes formation of genome compartments inCaenorhabditis elegansvia chromosome compaction and perinuclear anchoring

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2002068117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11459-11470 ◽

Cited By ~ 1

Author(s):

Qian Bian ◽

Erika C. Anderson ◽

Qiming Yang ◽

Barbara J. Meyer

Keyword(s):

Gene Expression ◽

Nuclear Periphery ◽

Chromosome Conformation ◽

C Elegans ◽

Genome Wide ◽

Central Regions ◽

In Trans ◽

Genomic Regions ◽

In Cis ◽

Gene Expression Levels

Genomic regions preferentially associate with regions of similar transcriptional activity, partitioning genomes into active and inactive compartments within the nucleus. Here we explore mechanisms controlling genome compartment organization inCaenorhabditis elegansand investigate roles for compartments in regulating gene expression. Distal arms ofC. eleganschromosomes, which are enriched for heterochromatic histone modifications H3K9me1/me2/me3, interact with each other bothin cisandin trans,while interacting less frequently with central regions, leading to genome compartmentalization. Arms are anchored to the nuclear periphery via the nuclear envelope protein CEC-4, which binds to H3K9me. By performing genome-wide chromosome conformation capture experiments (Hi-C), we showed that eliminating H3K9me1/me2/me3 through mutations in the methyltransferase genesmet-2andset-25significantly impaired formation of inactive Arm and active Center compartments.cec-4mutations also impaired compartmentalization, but to a lesser extent. We found that H3K9me promotes compartmentalization through two distinct mechanisms: Perinuclear anchoring of chromosome arms via CEC-4 to promote theircisassociation, and an anchoring-independent mechanism that compacts individual chromosome arms. In bothmet-2 set-25andcec-4mutants, no dramatic changes in gene expression were found for genes that switched compartments or for genes that remained in their original compartment, suggesting that compartment strength does not dictate gene-expression levels. Furthermore, H3K9me, but not perinuclear anchoring, also contributes to formation of another prominent feature of chromosome organization, megabase-scale topologically associating domains on X established by the dosage compensation condensin complex. Our results demonstrate that H3K9me plays crucial roles in regulating genome organization at multiple levels.

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The COP9 signalosome influences the epigenetic landscape of Arabidopsis thaliana

Bioinformatics ◽

10.1093/bioinformatics/bty1053 ◽

2018 ◽

Vol 35 (16) ◽

pp. 2718-2723 ◽

Cited By ~ 3

Author(s):

Tamir Tuller ◽

Alon Diament ◽

Avital Yahalom ◽

Assaf Zemach ◽

Shimshi Atar ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Arabidopsis Thaliana ◽

Gene Expression Regulation ◽

Developmental Pathways ◽

Cop9 Signalosome ◽

Supplementary Information ◽

Loss Of Function ◽

Genome Wide ◽

High Level

Abstract Motivation The COP9 signalosome is a highly conserved multi-protein complex consisting of eight subunits, which influences key developmental pathways through its regulation of protein stability and transcription. In Arabidopsis thaliana, mutations in the COP9 signalosome exhibit a number of diverse pleiotropic phenotypes. Total or partial loss of COP9 signalosome function in Arabidopsis leads to misregulation of a number of genes involved in DNA methylation, suggesting that part of the pleiotropic phenotype is due to global effects on DNA methylation. Results We determined and analyzed the methylomes and transcriptomes of both partial- and total-loss-of-function Arabidopsis mutants of the COP9 signalosome. Our results support the hypothesis that the COP9 signalosome has a global genome-wide effect on methylation and that this effect is at least partially encoded in the DNA. Our analyses suggest that COP9 signalosome-dependent methylation is related to gene expression regulation in various ways. Differentially methylated regions tend to be closer in the 3D conformation of the genome to differentially expressed genes. These results suggest that the COP9 signalosome has a more comprehensive effect on gene expression than thought before, and this is partially related to regulation of methylation. The high level of COP9 signalosome conservation among eukaryotes may also suggest that COP9 signalosome regulates methylation not only in plants but also in other eukaryotes, including humans. Supplementary information Supplementary data are available at Bioinformatics online.

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