Unknown,Transcriptomics,Genomics,Proteomics

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Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling

ABSTRACT: Histone H3 lysine27-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. Here, we establish a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles Polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing de-repression of PRC2 target genes and developmental perturbations. Similarly, a H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues. The histone H3K9 demethylase KDM3B/JHDM2 associates with H3K9M nucleosomes and its overexpression in Drosophila results in loss of H3K9 methylation levels and heterochromatic silencing defects. Here we establish histone lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation pathways that also function as biochemical reagents for capturing site-specific histone-modifying enzymes, thus providing molecular insight into chromatin-signaling pathways. RNA-seq of wing imaginal discs expressing either H3.3WT-FLAG-HA or H3.3K27M-FLAG-HA.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Ali Shilatifard

PROVIDER: E-GEOD-59891 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.

Herz Hans-Martin HM Morgan Marc M Gao Xin X Jackson Jessica J Rickels Ryan R Swanson Selene K SK Florens Laurence L Washburn Michael P MP Eissenberg Joel C JC Shilatifard Ali A

Science (New York, N.Y.) 20140801 6200

Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various ...[more]

PMID: 25170156

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Project description:An analysis of the transcriptional profiles of weak genetic perturbations generated via P-elements measured as heterozygotes in wing imaginal discs of Drosophila melanogaster. Abstract: A major objective of genomics is to elucidate the mapping between genotypic and phenotypic space as a step toward understanding how small changes in gene function can lead to elaborate phenotypic changes. One approach that has been utilized is to examine overall patterns of co-variation between phenotypic variables of interest, such as morphology, physiology and behavior, and underlying aspects of gene activity, in particular transcript abundance on a genome wide scale. Numerous studies have demonstrated that such patterns of co-variation occur, although these are often between samples with large numbers of unknown genetic differences (different strains, or even species) or perturbations of large effect (sexual dimorphism, or strong loss of function mutations), that may represent physiological changes outside of the normal experiences of the organism. We used weak mutational perturbations in genes affecting wing development in Drosophila melanogaster, that influence wing shape relative to a co-isogenic wild-type. We profiled transcription of 1150 genes expressed during wing development in 27 heterozygous mutants, as well as their co-isogenic wild type and one additional wild-type strain. Despite finding clear evidence of expression differences between mutants and wild-type, transcriptional profiles did not co-vary strongly with shape, suggesting that information from transcriptional profiling may not generally be predictive of final phenotype. We discuss these results in the light of possible attractor states of gene expression, and how this would affect interpretation of co-variation between transcriptional profiles and other phenotypes. Total RNA was extracted from pools of wing imaginal discs for each mutant strain as well as for their co-isogenic wild-type, and one additional wild-type strain. RNA was extracted using a modified protocol using the Qiagen RNAeasy kit.

Dataset Information

Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling

Publications

Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.

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