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Expression noise and acetylation profiles distinguish HDAC functions.

ABSTRACT: Gene expression shows a significant variation (noise) between genetically identical cells. Noise depends on the gene expression process regulated by the chromatin environment. We screened for chromatin factors that modulate noise in S. cerevisiae and analyzed the results using a theoretical model that infers regulatory mechanisms from the noise versus mean relationship. Distinct activities of the Rpd3(L) and Set3 histone deacetylase complexes were predicted. Both HDACs repressed expression. Yet, Rpd3(L)C decreased the frequency of transcriptional bursts, while Set3C decreased the burst size, as did H2B monoubiquitination (ubH2B). We mapped the acetylation of H3 lysine 9 (H3K9ac) upon deletion of multiple subunits of Set3C and Rpd3(L)C and of ubH2B effectors. ubH2B and Set3C appear to function in the same pathway to reduce the probability that an elongating PolII produces a functional transcript (PolII processivity), while Rpd3(L)C likely represses gene expression at a step preceding elongation.

SUBMITTER: Weinberger L

PROVIDER: S-EPMC3408861 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Expression noise and acetylation profiles distinguish HDAC functions.

Weinberger Leehee L Voichek Yoav Y Tirosh Itay I Hornung Gil G Amit Ido I Barkai Naama N

Molecular cell 20120607 2

Gene expression shows a significant variation (noise) between genetically identical cells. Noise depends on the gene expression process regulated by the chromatin environment. We screened for chromatin factors that modulate noise in S. cerevisiae and analyzed the results using a theoretical model that infers regulatory mechanisms from the noise versus mean relationship. Distinct activities of the Rpd3(L) and Set3 histone deacetylase complexes were predicted. Both HDACs repressed expression. Yet, ...[more]

PMID: 22683268

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Project description:Histone acetylation, balanced by histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes, affects dynamic transitions of chromatin structure to regulate transcriptional accessibility. However, little is known about the interplay between HAT and HDAC complexes in Fusarium graminearum, a causal agent of Fusarium Head Blight (FHB) that uniquely contains chromosomal regions enriched for house-keeping or infection-related genes. In this study, we identified the ortholog of the human inhibitor of growth (ING1) gene in F. graminearum (FNG1) and found that it specifically interacts with the FgEsa1 HAT of the NuA4 complex. Deletion of FNG1 led to severe growth defects and blocked conidiation, sexual reproduction, DON production, and plant infection. The fng1 mutant was normal in H3 acetylation but significantly reduced in H4 acetylation. A total of 34 spontaneous suppressors of fng1 with faster growth rate were isolated. Most of them were still defective in sexual reproduction and plant infection. Thirty two of them had mutations in orthologs of yeast RPD3, SIN3, and SDS3, three key components of the yeast Rpd3L HDAC complex. Four mutations in these three genes were verified to suppress the defects of fng1 mutant in growth and H4 acetylation. The rest two suppressor strains had a frameshift or nonsense mutation in a glutamine-rich hypothetical protein that may be a novel component of the FgRpd3 HDAC complex in filamentous fungi. FgRpd3, like Fng1, localized in euchromatin. Deletion of FgRPD3 resulted in severe growth defects and elevated H4 acetylation. In contract, the Fgsds3 deletion mutant had only a minor reduction in growth rate but FgSIN3 appeared to be an essential gene. RNA-seq analysis revealed that 48.1% and 54.2% of the genes with altered expression levels in the fng1 mutant were recovered to normal expression levels in two suppressor strains with mutations in FgRPD3 and FgSDS3, respectively. Taken together, our data showed that Fng1 is important for H4 acetylation as a component of the NuA4 complex and functionally related to the FgRpd3 HDAC complex for transcriptional regulation of genes important for growth, conidiation, sexual reproduction, and plant infection in F. graminearum.

Project description:ObjectivesMicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that are commonly dysregulated in colorectal tumors. The objective of this study was to identify smaller subsets of highly predictive miRNAs.MethodsData come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. Tissue samples were available for 1,953 individuals, of which 1,894 had carcinoma tissue and 1,599 had normal mucosa available for statistical analysis. Agilent Human miRNA Microarray V.19.0 was used to generate miRNA expression profiles; validation of expression levels was carried out using quantitative PCR. We used random forest analysis and verified findings with logistic modeling in separate data sets. Important microRNAs are identified and bioinformatics tools are used to identify target genes and related biological pathways.ResultsWe identified 16 miRNAs for colon and 17 miRNAs for rectal carcinoma that appear to differentiate between carcinoma and normal mucosa; of these, 12 were important for both colon and rectal cancer, hsa-miR-663b, hsa-miR-4539, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-4506, hsa-miR-92a-3p, hsa-miR-93-5p, hsa-miR-145-5p, hsa-miR-3651, hsa-miR-378a-3p, and hsa-miR-378i. Estimated misclassification rates were low at 4.83% and 2.5% among colon and rectal observations, respectively. Among independent observations, logistic modeling reinforced the importance of these miRNAs, finding the primary principal components of their variation statistically significant (P<0.001 among both colon and rectal observations) and again producing low misclassification rates. Repeating our analysis without those miRNAs initially identified as important identified other important miRNAs; however, misclassification rates increased and distinctions between remaining miRNAs in terms of classification importance were reduced.ConclusionsOur data support the hypothesis that while many miRNAs are dysregulated between carcinoma and normal mucosa, smaller subsets of these miRNAs are useful and informative in discriminating between these tissues.

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Expression noise and acetylation profiles distinguish HDAC functions.

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Expression noise and acetylation profiles distinguish HDAC functions.

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