Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Nkx2.2, Nkx6.1, Olig2, and Gli3 genomic binding regions and overexpression in neural progenitors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Yuichi Nishi

PROVIDER: E-GEOD-65462 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A direct fate exclusion mechanism by Sonic hedgehog-regulated transcriptional repressors.

Nishi Yuichi Y Zhang Xiaoxiao X Jeong Jieun J Peterson Kevin A KA Vedenko Anastasia A Bulyk Martha L ML Hide Winston A WA McMahon Andrew P AP

Development (Cambridge, England) 20150820 19

Sonic hedgehog (Shh) signaling patterns the vertebrate spinal cord by activating a group of transcriptional repressors in distinct neural progenitors of somatic motor neuron and interneuron subtypes. To identify the action of this network, we performed a genome-wide analysis of the regulatory actions of three key ventral determinants in mammalian neural tube patterning: Nkx2.2, Nkx6.1 and Olig2. Previous studies have demonstrated that each factor acts predominantly as a transcriptional repressor ...[more]

PMID: 26293298

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Project description:BS69 (aka ZMYND11) was initially discovered as a direct target of adenoviral E1A oncoprotein1. Subsequent studies implicated BS69 as a tumor suppressor and a transcriptional regulator2. But exactly how BS69 regulates gene expression has remained elusive. BS69 contains tandemly arranged PHD, BROMO and PWWP domains, which are known to function as chromatin recognition modalities. Here we show that BS69 selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3) via these chromatin recognition modules. Using a proteomics approach, we further identified association of BS69 with a host of RNA splicing regulators including EFTUD2 and other U5 snRNP components of the spliceosome. Remarkably, RNA-seq analysis shows that BS69 mainly regulates intron retention (IR), which is one of the least well-understood RNA alternative splicing events in mammalian cells. Specifically, loss of BS69 results in a decrease in IR, while in contrast, knockdown of EFTUD2 leads to an increase in IR, consistent with its role as a core member of the splicesome machinery. Importantly, wildtype BS69, but not a BS69 mutant defective in its interaction with EFTUD2, rescues the IR events. We also show that knockdown of SETD2, the main enzyme that mediates H3K36 trimethylation3, similarly results in a decreased retention of the same introns regulated by BS69. Significantly, a BS69 mutant unable to bind H3.3K36me3 in vitro fails to rescue the reduced IR phenotype associated with the loss of BS69. Taken together, our findings identify an antagonistic relationship between BS69 and the core splicing machinery and demonstrate that BS69-mediated RNA splicing regulation is dependent both on its ability to bind chromatin decorated by H3K36me3 and its ability to physically interact with the core spliceosome machinery. Our study reveals a novel and unexpected role of BS69 in connecting histone H3.3K36 trimethylation to regulated RNA splicing, providing significant new insights into chromatin regulation of RNA splicing. HeLaS cells stably expressing BS69 were used for HA-tagged BS69 ChIP-seq. HeLa cells were used for BS69 ChIP-seq. HeLa cells were used for H3K36me3 ChIP-seq.

Dataset Information

Nkx2.2, Nkx6.1, Olig2, and Gli3 genomic binding regions and overexpression in neural progenitors

Publications

A direct fate exclusion mechanism by Sonic hedgehog-regulated transcriptional repressors.

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