Dataset Information

Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

ABSTRACT: Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself, by supporting TFIIH (CDK7)- and P-TEFb (CDK9)-mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in MM functioning through regulation of MYC-target gene transcription, and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.

SUBMITTER: Ohguchi H

PROVIDER: S-EPMC8265280 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

Ohguchi Hiroto H Park Paul M C PMC Wang Tingjian T Gryder Berkley E BE Ogiya Daisuke D Kurata Keiji K Zhang Xiaofeng X Li Deyao D Pei Chengkui C Masuda Takeshi T Johansson Catrine C Wimalasena Virangika K VK Kim Yong Y Hino Shinjiro S Usuki Shingo S Kawano Yawara Y Samur Mehmet K MK Tai Yu-Tzu YT Munshi Nikhil C NC Matsuoka Masao M Ohtsuki Sumio S Nakao Mitsuyoshi M Minami Takashi T Lauberth Shannon S Khan Javed J Oppermann Udo U Durbin Adam D AD Anderson Kenneth C KC Hideshima Teru T Qi Jun J

Blood cancer discovery 20210410 4

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output <i>in vitro</i> and <i>in vivo</i>. Using ...[more]

PMID: 34258103

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Project description:Patterns of methylation at lysine 4 and 27 of histone H3 have been associated with states of gene activation and repression that are developmentally regulated and are thought to underlie the establishment of lineage specific gene expression programs. Recent studies have provided fundamental insight into the problem of lineage specification by comparing global changes in chromatin and transcription between ES and neural stem (NS) cells, points respectively of departure and arrival for neural commitment. With these maps of the differentiated state in place, a central task is now to unravel the chromatin dynamics that enables these differentiation transitions. In particular, the observation that lineage-specific genes repressed in ES cells by Polycomb-mediated H3-K27 trimethylation (H3-K27me3) are demethylated and derepressed in differentiated cells posited the existence of a specific H3-K27 demethylase.In order to gain insight into the epigenetic transitions that enable lineage specification, we investigated the early stages of neural commitment using as model system the monolayer differentiation of mouse ES cells into neural stem (NS) cells. Starting from a comprehensive profiling of JmjC-domain genes, we report here that Jmjd3, recently identified as a H3-K27me3 specific demethylase, controls the expression of key regulators and markers of neurogenesis and is required for commitment to the neural lineage.Our results demonstrate the relevance of an enzymatic activity that antagonizes Polycomb regulation and highlight different modalities through which the dynamics of H3-K27me3 is related to transcriptional output. By showing that the H3-K27 demethylase Jmjd3 is required for commitment to the neural lineage and that it resolves the bivalent domain at the Nestin promoter, our work confirms the functional relevance of bivalent domain resolution that had been posited on the basis of the genome-wide correlation between their controlled resolution and differentiation. In addition, our data indicate that the regulation of H3-K27me3 is highly gene- and context- specific, suggesting that the interplay of methyltransferases and demethylases enables the fine-tuning more than the on/off alternation of methylation states.

Dataset Information

Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

Publications

Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

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