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ZMYND8 reads the dual histone mark H3K4me1-H3K14ac to antagonize the expression of metastasis-linked genes

ABSTRACT: Histone acetylation, including acetylated H3K14 (H3K14ac), is generally linked to gene activation. Monomethylated histone H3 lysine 4 (H3K4me1), together with other gene-activating marks, denotes active genes. In contrast to usual gene-activating functions of H3K14ac and H3K4me1, we here show that the dual histone modification mark H3K4me1-H3K14ac is recognized by ZMYND8 (also called RACK7) and functions to counteract gene expression. We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8 antagonizes the expression of metastasis-linked genes, and its knockdown increases the cellular invasiveness in vitro and in vivo. The plant homeodomain (PHD) and Bromodomain cassette in ZMYND8 mediates the combinatorial recognition of H3K4me1-H3K14ac and H3K4me0-H3K14ac by ZMYND8. These findings uncover an unexpected role for the signature H3K4me1-H3K14ac in attenuating gene expression and reveal a previously unknown metastasis-suppressive epigenetic mechanism in which ZMYND8's PHD-Bromo cassette couples H3K4me1-H3K14ac with repression of metastasis-linked genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE82260 | GEO | 2016/07/28

SECONDARY ACCESSION(S): PRJNA324450

REPOSITORIES: GEO

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ZMYND8 reads the dual histone mark H3K4me1-H3K14ac to antagonize the expression of metastasis-linked genes

Project description:Histone acetylation, including acetylated H3K14 (H3K14ac), is generally linked to gene activation. Monomethylated histone H3 lysine 4 (H3K4me1), together with other gene-activating marks, denotes active genes. In contrast to usual gene-activating functions of H3K14ac and H3K4me1, we here show that the dual histone modification mark H3K4me1-H3K14ac is recognized by ZMYND8 (also called RACK7) and functions to counteract gene expression. We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8 antagonizes the expression of metastasis-linked genes, and its knockdown increases the cellular invasiveness in vitro and in vivo. The plant homeodomain (PHD) and Bromodomain cassette in ZMYND8 mediates the combinatorial recognition of H3K4me1-H3K14ac and H3K4me0-H3K14ac by ZMYND8. These findings uncover an unexpected role for the signature H3K4me1-H3K14ac in attenuating gene expression and reveal a previously unknown metastasis-suppressive epigenetic mechanism in which ZMYND8's PHD-Bromo cassette couples H3K4me1-H3K14ac with repression of metastasis-linked genes. i) ChIP-Seq data of ZMYND8, JARID1D, H3K4me1, H3K14ac, H3K4me3, and H3K27me3 in normal DU145 cells. ii) ChIP-Seq data of H3K4me1 and H3K4me3 in shLuciferase-, shJARID1D-, or shZMYND8-treated DU145 cells. iii) RNA-Seq data in shLuciferase-, shJARID1D-, or shZMYND8-treated DU145 cells.

2016-07-28 | E-GEOD-82260 | biostudies-arrayexpress

Homo sapiens

Project description:ZMYND8 reads the dual histone mark H3K4me1-H3K14ac to antagonize the expression of metastasis-linked genes

| PRJNA324450 | ENA

Recognition of a pediatric glioblastoma-associated histone mutation by chromatin reader ZMYND8 promotes tumorigenesis

Project description:Histone H3 point mutations have recently been identified in pediatric brain cancers, including missense mutations on histone H3 at positions 27 (lysine to methionine; K27M) and 34 (glycine to arginine, G34R), respectively. H3K27M mutations are associated with a majority of pediatric Diffuse Intrinsic Pontine Pediatric Glioma (DIPG) cases, while H3.3G34R is found in pediatric glioblastoma (GBM) arising in the cerebral cortex1,2. While the mechanisms of H3K27M-driven tumorigenesis are beginning to unravel, much less is known about the H3.3G34R mutation. Here, we provide both biochemical and structural evidence that the PHD (plant homedomain) domain of the enhancer-binding protein, RACK7 (ZMYND8), recognizes H3.3G34R mutant histone via a mechanism distinct from other PHD domains. In an H3.3G34R-expressing neuronal precursor cell line, we demonstrate that RACK7 is aberrantly recruited to enhancers bound by H3.3G34R, resulting in the down-regulation of many neuronal genes, and the up-regulation of oncogenes such as MYC. Neural precursor cells expressing H3.3G34R showed enhanced tumor growth when injected subcutaneously. Inhibiting RACK7 binding to H3.3G34R reduces tumor size and alters gene expression, suggesting that H3.3G34R regulation of enhancers via RACK7 promotes tumorigenesis. Specifically, we show that both the gene expression and tumor size regulation are critically dependent on the physical interaction of H3.3G34R with RACK7. Both regulations are compromised in the absence of RACK7, and can be rescued by wildtype, but not an H3.3G34R-binding defective, RACK7. Taken together, we have identified a reader for H3.3G34R and demonstrate that RACK7 binding to H3.3G34R alters enhancer activity to directly suppress neural gene transcription and to increase oncogenic propensity of neural precursor cells, thus providing a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.

2024-04-14 | GSE99979 | GEO

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (ChIP-Seq I)

Project description:Primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1), and the conversion to active enhancers involves acetylation of histone H3K27 (H3K27Ac). However, whether active enhancers are regulated remains unclear. Here we report a biochemical complex consisting of a potential chromatin reader (RACK7) and a histone demethylase (KDM5C) that occupies many active enhancers in a breast cancer cell line. Loss of RACK7 or KDM5C results in hyperactive enhancers marked by H3K4me3 and H3K27Ac, and characterized by an increased eRNA transcription and elevated expression of nearby genes. Loss of RACK7 or KDM5C also leads to increased cell invasion and migration, and enhanced tumor growth. We propose that RACK7/KDM5C functions as an enhancer âbrakeâ to ensure appropriate enhancer activities in the cell. Our findings provide important insight into histone H3K4 methylation dynamics at enhancers and reveal a molecular mechanism that controls the activities of active enhancers, which when compromised, can contribute to tumorigenesis. ChIP-seq data of RACK7, KDM5C and histone modifications in parental and RACK7-KO ZR-75-30 cells.

2016-04-07 | E-GEOD-71323 | biostudies-arrayexpress

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (ChIP-Seq II)

2016-04-07 | E-GEOD-76637 | biostudies-arrayexpress

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (RNA-Seq I)

2016-04-07 | E-GEOD-71325 | biostudies-arrayexpress

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (RNA-Seq II)

2016-04-07 | E-GEOD-71326 | biostudies-arrayexpress

Catalytic-independent functions of INTAC confer sensitivity to BET inhibition [CUT&Tag]

Project description:Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs with poorly understood mechanisms. Using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary module of the INTAC complex, a global regulator of polymerase pause-release dynamics. This process bypasses a requirement for INTAC's catalytic activities and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8–KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.

2024-10-11 | GSE274475 | GEO

Catalytic-independent functions of INTAC confer sensitivity to BET inhibition [RNA-seq]

2024-10-11 | GSE274473 | GEO

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (RNA-Seq II)

Project description:Primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1), and the conversion to active enhancers involves acetylation of histone H3K27 (H3K27Ac). However, whether active enhancers are regulated remains unclear. Here we report a biochemical complex consisting of a potential chromatin reader (RACK7) and a histone demethylase (KDM5C) that occupies many active enhancers in a breast cancer cell line. Loss of RACK7 or KDM5C results in hyperactive enhancers marked by H3K4me3 and H3K27Ac, and characterized by an increased eRNA transcription and elevated expression of nearby genes. Loss of RACK7 or KDM5C also leads to increased cell invasion and migration, and enhanced tumor growth. We propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activities in the cell. Our findings provide important insight into histone H3K4 methylation dynamics at enhancers and reveal a molecular mechanism that controls the activities of active enhancers, which when compromised, can contribute to tumorigenesis.

2016-04-07 | GSE71326 | GEO

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