Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of Myt1 as a subunit of the neural cell type-specific LSD1 complex

ABSTRACT: Regulation of spatiotemporal gene expression in higher eukaryotic cells is critical for the precise and orderly development of undifferentiated progenitors into committed cell types of the adult. Recently, dynamic epigenomic regulation, including chromatin remodeling and histone modifications by transcriptional coregulator complexes, has been shown to be involved in transcriptional regulation. Precisely how these coregulator complexes exert their cell-type and developing stage-specific activity is largely unknown. In this study, we aimed to isolate the histone demethylase LSD1 complex from neural cells by biochemical purification. In so doing, we identified MyT1 as a novel LSD1 complex component. MyT1 is a neural cell-specific zinc finger factor and it forms a stable multiprotein complex with LSD1 through direct interaction. Target gene analysis using microarray and ChIP assays revealed several genes, including PTEN, that were directly regulated by the LSD1-MyT1 complex. Knockdown of either LSD1 or MyT1 derepressed the expression of endogenous target genes and inhibited cell proliferation of a neuroblastoma cell line, Neuro2a. We propose that formation of tissue-specific combinations of coregulator complexes is a critical mechanism for tissue-specific transcriptional regulation. Neuro2a cells were treated with either siControl, siLSD1 or siMyT1 for 48 h (n=3)

ORGANISM(S): Mus musculus

SUBMITTER: Atsushi Yokoyama

PROVIDER: E-GEOD-49685 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Identification of myelin transcription factor 1 (MyT1) as a subunit of the neural cell type-specific lysine-specific demethylase 1 (LSD1) complex.

Yokoyama Atsushi A Igarashi Katsuhide K Sato Tetsuya T Takagi Kiyoshi K Otsuka I Maky M Shishido Yurina Y Baba Takashi T Ito Ryo R Kanno Jun J Ohkawa Yasuyuki Y Morohashi Ken-Ichirou K Sugawara Akira A

The Journal of biological chemistry 20140514 26

Regulation of spatiotemporal gene expression in higher eukaryotic cells is critical for the precise and orderly development of undifferentiated progenitors into committed cell types of the adult. It is well known that dynamic epigenomic regulation (including chromatin remodeling and histone modifications by transcriptional coregulator complexes) is involved in transcriptional regulation. Precisely how these coregulator complexes exert their cell type and developing stage-specific activity is lar ...[more]

PMID: 24828497

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Project description:Epigenetic regulation of gene expression by histone modification has emerged as a major facet of physiologic and disease processes. As a result, there has been intense interest in developing epigenetic therapies leading to the discovery of small molecule agents that target proteins involved in histone modification. Several histone deacetylase (HDAC) inhibitors are now approved drugs for a specialized group of hematologic malignancies but not yet for a wider range of cancer types including solid tumors. One of the conceptual challenges in targeting HDACs is that even selective class I HDAC inhibitors likely impact these deacetylase activities indiscriminately across a range of distinct HDAC-containing multiprotein complexes. Such broad cellular effects may result in a narrow therapeutic window between disease efficacy and toxicity. Among HDAC complexes, the CoREST complex, which includes HDAC1 or its close paralog HDAC2, the scaffolding protein CoREST, and lysine specific demethylase 1 (LSD1) has attracted special interest. Here we report corin2, designed to dually inhibit the CoREST complex major enzymatic activities, lysine specific demethylase 1 (LSD1) and HDACs 1/2. Corin2 is a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin2 selectively targets the CoREST complex and shows more sustained inhibition of the CoREST complex HDAC activity than entinostat. Cell-based experiments demonstrate that corin2 exhibits a superior anti-proliferative profile against several melanoma lines compared to its parent monofunctional HDAC and LSD1 inhibitors (alone or in combination) but is less toxic to non-cancerous primary human melanocytes. Transcriptomics analysis shows that corin2 is a more powerful inducer of tumor suppressor genes relative to the parent HDAC and LSD1 compounds (alone or in combination). Genetic knockdown of CoREST or LSD1 in cancer cell lines abolishes the differences in potency of corin2 vs. entinostat, suggesting that corin2's favorable pharmacologic effects rely on an intact CoREST complex. Corin2 was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that selectively target particular epigenetic regulatory complexes and offer unique therapeutic opportunities. We characterized the gene expression changes uniquely related to dual inhibition of HDAC1/2 and LSD1 as part of the CoREST complex to identify genes associated with our dual inhibitor's (corin2) antiproliferative mechanism of action in melanoma cells. Transcriptomics analysis shows that corin2 is a more powerful inducer of tumor suppressor genes relative to the parent HDAC and LSD1 compounds (alone or in combination).

Dataset Information

Identification of Myt1 as a subunit of the neural cell type-specific LSD1 complex

Publications

Identification of myelin transcription factor 1 (MyT1) as a subunit of the neural cell type-specific lysine-specific demethylase 1 (LSD1) complex.

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