Unknown,Transcriptomics,Genomics,Proteomics

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The tumor suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements

ABSTRACT: In Drosophila, defects in asymmetric cell division can result in the formation of stem cell derived tumors. Here, we reveal a different mechanism that can result in the formation of very similar terminal brain tumor phenotypes. We demonstrate that brain tumors in l(3)mbt mutants originate from overproliferation of neuroepithelial cells in the optic lobes caused by de-repression of target genes in the Salvador-Warts-Hippo (SWH) pathway. We use ChIP-seq to identify L(3)mbt-binding sites and show that L(3)mbt binds to chromatin insulator elements. Mutating l(3)mbt or inhibiting the insulator protein mod(mdg4) results in upregulation of SWH pathway reporters. As l(3)mbt tumors are rescued by mutations in bantam or yorkie or by overexpression of expanded the deregulation of SWH pathway target genes is an essential step in brain tumor formation. Our data reveal that very different primary defects can result in the formation of brain tumors, which behave quite similarly in their advanced stages. Examination of l(3)mbt binding in third instar larval brain and wing/haltere/third leg imaginal discs tissue.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Jonas Steinmann

PROVIDER: E-GEOD-29206 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements.

Richter Constance C Oktaba Katarzyna K Steinmann Jonas J Müller Jürg J Knoblich Juergen A JA

Nature cell biology 20110821 9

In Drosophila, defects in asymmetric cell division often result in the formation of stem-cell-derived tumours. Here, we show that very similar terminal brain tumour phenotypes arise through a fundamentally different mechanism. We demonstrate that brain tumours in l(3)mbt mutants originate from overproliferation of neuroepithelial cells in the optic lobes caused by derepression of target genes in the Salvador-Warts-Hippo (SWH) pathway. We use ChIP-sequencing to identify L(3)mbt binding sites and ...[more]

PMID: 21857667

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Project description:DNA methylation is a dynamic process through which specific chromatin modifications can be stably transmitted from parent to daughter cells. A large body of work has suggested that DNA methylation influences gene expression by silencing gene promoters. However, these conclusions were drawn from data focused mostly on promoter regions. With regards to the entire genome, it is unclear how methylation and gene transcription patterns are related during vertebrate development. To identify the genome-wide distribution of CpG methylation we created series of high-resolution methylome maps of Danio rerio embryos during development and in mature, differentiated tissues. We find that embryonic and terminal tissues have unique methylation signatures in CpG islands and repetitive sequences. Fully differentiated tissues have increased CpG and LTR methylation and decreased SINE methylation relative to embryonic tissues. Unsupervised clustering analyses reveal that the embryonic and terminal tissues can be classified solely by their methylation patterning. Novel analyses also identify a previously undescribed genome-wide exon methylation signature. We also compared whole genome methylation with genome-wide mRNA expression levels using publicly available RNA-seq datasets. These comparisons revealed previously unrecognized relationships between gene-expression, alternative splicing and exon methylation. Surprisingly, we find that exonic methylation is a better predictor of mRNA expression level than promoter methylation. We also found that transcriptionally skipped exons have significantly less methylation than retained exons. Our integrative analyses reveal highly complex interplay between gene expression, alternative splicing, development, and methylation patterning in zebrafish. MBD-Seq with whole embryos (sperm, 1cell, mbt, 3dpf) and adult tissues (eye, brain, heart, liver) Please note that the mePoor brain lane4 sample raw data files were used as loading/sequencing controls for the following meRich.lane4 samples; eye_meRich.lane4 heart_meRich.lane4 liver_meRich.lane4 The mePoor brain lane5 sample raw data files were used as loading/sequencing controls for the following meRich.lane5 samples; 1cell_meRich.lane5 mbt_meRich.lane5 sperm_meRich.lane5

Dataset Information

The tumor suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements

Publications

The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements.

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