Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA290516 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2121850.fastq.gz | Fastqsanger.gz | |||
| SRR2121851.fastq.gz | Fastqsanger.gz | |||
| SRR2121852.fastq.gz | Fastqsanger.gz | |||
| SRR2121853.fastq.gz | Fastqsanger.gz | |||
| SRR2121854.fastq.gz | Fastqsanger.gz |
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Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. ChIP-Seq for regulatory factors of BRD4, NSD3, CHD8 and histone modification H3K36me2 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)
2015-12-17 | E-GEOD-71183 | biostudies-arrayexpress
Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. PolyA+ (illumine TruSeq)/not-so-random (NSR) primers selected RNA-Seq for shRNA/sgRNA-expressing MLL-AF9 transformed acute myeloid leukemia cells (RN2).
2015-12-17 | E-GEOD-71185 | biostudies-arrayexpress
Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription.
2015-12-17 | GSE71183 | GEO
Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription.
2015-12-17 | GSE71185 | GEO
Project description:NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler (ChIP-Seq)
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Project description:NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler
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Project description:Sequencing studies of autism spectrum disorder (ASD) cases have revealed a causal role for mutations to chromatin remodeling genes. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeler with one of the highest de novo mutation rates in sporadic ASD. However, the relationship between CHD8 genomic function and autism-relevant biology remains poorly elucidated. CHD8 binding studies have relied on Chromatin Immunoprecipitation followed by sequencing (ChIP-seq), but these datasets exhibit significant variation. ChIP-seq has technical limitations in the context of weak or indirect protein-DNA interactions or when high-performance antibodies are unavailable. Thus, complementary approaches are needed to establish CHD8 genomic targets. Here we used Targeted DamID in utero to characterize CHD8 binding activity in the developing embryonic mouse cortex. CHD8 Targeted DamID followed by sequencing (CHD8 TaDa-seq) revealed binding at previously identified genomic targets as well as at genes sensitive to Chd8 haploinsufficiency. CHD8 TaDa-seq showed greater sensitivity for CHD8 binding near a subset of genes specific to brain development and neuron function. These studies establish TaDa-seq as a useful alternative for mapping protein-DNA interactions in vivo and provide insights into the relationship between chromatin remodeling by CHD8 and autism-relevant pathophysiology associated with CHD8 mutations.
2021-01-18 | GSE165002 | GEO
Project description:The loss-of-function mutations in the chromatin remodeler CHD8, a high-risk factor in autism spectrum disorder (ASD), lead to severe developmental delay, however, the underlying mechanisms remains elusive. Here, we use transcriptome and genomic occupancy reveal that CHD8 regulates chromatin accessibility and activates neurogenesis-related genes for cortical neurogenesis.
2022-10-17 | GSE148608 | GEO
Project description:Chromatin remodeler CHD8 in CNS myelination and remyelination
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Project description:Mutations in ATP-dependent chromatin remodeler CHD8 cause one of the most frequent monogenetic forms of autism and is associated with brain overgrowth. Nevertheless, the activities of CHD8 in autism-relevant cell types are still poorly understood. Here, we purify the CHD8 protein from human neural stem cells and determine its interaction partners using mass spectrometry. We identify the TRRAP complex, a coactivator of MYC and E2F transcription factors, as a prominent CHD8 interaction partner. CHD8 colocalizes genome-wide with TRRAP and bind together at MYC and E2F target gene promoters in human neural stem cells. Depletion of CHD8 or TRRAP in human neural stem cells shows downregulation of MYC and E2F target genes as the most prominent gene-regulatory events. MYC and E2F transcription factors are established oncogenes known to regulate cell growth. Our results link CHD8 to TRRAP and suggest they act together in facilitating the regulation of MYC and E2F target genes in neural stem cells.
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