The X-Linked Mental Retardation Gene SMCX/JARID1C Defines a Family of Histone H3 Lysine 4 Demethylases

Iwase, Shigeki; Lan, Fei; Bayliss, Peter E.; Torre-Ubieta, Luis de la; Huarte, Maite; Qi, Hank H.; Whetstine, Johnathan R.; Bonni, Azad; Roberts, Thomas M.; Shi, Yang

doi:10.1016/j.cell.2007.02.017

Cited by 623 publications

(680 citation statements)

References 49 publications

(84 reference statements)

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“…This hypothesis is consistent with a growing list of epigenetic regulators implicated in XLMR, including: the SMCX (KDM5C/JARID1C) (38,39), neuronrestrictive silencing factor NRSF/REST (40), and plant homeodomain finger 8 (38,41). Our data demonstrating that Cul4B can serve as a translational regulator links it with another XLMR protein, fragile-X mental retardation protein, mutations of which result in the most common single gene inherited mental retardation.…”

Section: Discussionsupporting

confidence: 71%

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Pfeiffer

Brooks

2012

The Journal of Immunology

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TNF-α is a central mediator of inflammation and critical for host response to infection and injury. TNF-α biosynthesis is controlled by transcriptional and posttranscriptional mechanisms allowing for rapid, transient production. Tristetraprolin (TTP) is an AU-rich element binding protein that regulates the stability of the TNF-α mRNA. Using a screen to identify TTP-interacting proteins, we identified Cullin 4B (Cul4B), a scaffolding component of the Cullin ring finger ligase family of ubiquitin E3 ligases. Short hairpin RNA knockdown of Cul4B results in a significant reduction in TNF-α protein and mRNA in LPS-stimulated mouse macrophage RAW264.7 cells as well as a reduction in TTP protein. TNF-α message t1/2 was reduced from 69 to 33 min in LPS-stimulated cells. TNF-3′ untranslated region luciferase assays utilizing wild-type and mutant TTP-AA (S52A, S178A) indicate that TTP function is enhanced in Cul4B short hairpin RNA cells. Importantly, the fold induction of TNF-α mRNA polysome loading in response to LPS stimulation is reduced by Cul4B knockdown. Cul4B is present on the polysomes and colocalizes with TTP to exosomes and processing bodies, which are sites of mRNA decay. We conclude that Cul4B licenses the TTP-containing TNF-α messenger ribonucleoprotein for loading onto polysomes, and reduction of Cul4B expression shunts the messenger ribonucleoproteins into the degradative pathway.

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Section: Discussionsupporting

confidence: 71%

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Pfeiffer

Brooks

2012

The Journal of Immunology

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“…Both amine oxidases and JmjC-domain proteins demethylate by oxidation or hydroxylation, processes directly affected under hypoxia [21]. One potential mechanism driving increased H3K4me3 may be hypoxia-induced inactivation of H3K4me3-specfic histone demethylases, which utilize molecular oxygen during enzymatic removal of methyl groups [22][23][24]. The observed modifications of histones provide a hypoxia-regulated platform for binding and interactions of additional chromatin modifiers, remodelers or regulators of transcription, further amplifying gene-specific response to hypoxic stress.…”

Section: Hypoxia-induced Gene-specific Histone Modificationsmentioning

confidence: 99%

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

Johnson¹,

Denko²,

Barton³

2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

236

207

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Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither cell type-specific nor HIF-1-dependent. Despite overall repression, hypoxia induces a pool of histone modifications typically associated with transcriptional activation or repression. Chromatin immunoprecipitation analyses showed that this global mixture of hypoxia-modified histones is sorted in a gene-specific manner to correlate with transcriptional response to hypoxia. Exceptions to this were unexpected increases in H3K4me3 levels, typically associated with transcriptional activation, and decreased H3K27me3 levels, generally a marker of transcriptional silencing, at core promoters of both hypoxia-activated andrepressed genes. These data suggest that a novel signature of chromatin modifications is induced under hypoxic stress, which may play a role in gene regulatory switches active in proliferating tumor cells undergoing cycles of hypoxia and reoxygenation.

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“…Within this intersectional group of genes, the melanoma-relevant genes JAG-1 [48][49][50] and CDK6 [35][36][37][38] were included as well as 1 new candidate melanoma gene, DYRK1A, which was reported to be downregulated in highly metastatic melanoma cells. [63][64][65] RBP2-H1/JARID1B re-expression re-constitutes anti-tumorigenic mechanisms in melanoma cells…”

Section: Rbp2-h1/jarid1b Binds To a Multitude Of Human Chromosomal Rementioning

confidence: 99%

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

Roesch

Mueller²,

Stempfl

et al. 2007

Intl Journal of Cancer

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The RBP2-H1/JARID1B nuclear protein belongs to the ARID family of DNA-binding proteins and is a potential tumor suppressor that is lost during melanoma development. As we have recently shown, one physiological function of RBP2-H1/JARID1B is to exert cell cycle control via maintenance of active retinoblastoma protein. We now add new evidence that RBP2-H1/JARID1B can also directly regulate gene transcription in a reporter assay system, either alone or as part of a multimolecular complex together with the developmental transcription factors FOXG1b and PAX9. In melanoma cells, chromatin immunoprecipitation combined with promoter chip analysis (ChIP-on-chip) suggests a direct binding of re-expressed RBP2-H1/JARID1B to a multitude of human regulatory chromosomal elements (promoters, enhancers and introns). Among those, a set of 23 genes, including the melanoma relevant genes CDK6 and JAG-1 could be confirmed by cDNA microarray analyses to be differentially expressed after RBP2-H1/JARID1B re-expression. In contrast, in nonmelanoma HEK 293 cells, RBP2-H1/JARID1B overexpression only evokes a minor transcriptional response in cDNA microarray analyses. Because the transcriptional regulation in melanoma cells is accompanied by an inhibition of proliferation, an increase in caspase activity and a partial cell cycle arrest in G1/0, our data support an anti-tumorigenic role of RBP2-H1/JARID1B in melanocytic cells. ' 2007 Wiley-Liss, Inc.Key words: melanoma; transcription; gene expression; retinoblastoma protein binding protein; apoptosisIn 1999, our group detected a gene transcript suppressed by UV-B in normal human melanocytes (Acc. No. AF087481, 1 ). Based on its homology to the previously described RBP2, 2 this new gene was termed retinoblastoma binding protein 2-homolog 1 (RBP2-H1). Subsequent expression studies revealed a frequent loss of RBP2-H1 in the majority of advanced and metastatic melanomas in vivo and in many melanoma cell lines, whereas benign melanocytic tumors, normal tissues and other cancer types mostly retain RBP2-H1. 1,3 Recently, we showed that RBP2-H1 has a tumor suppressive activity partly due to binding and stabilization of hypophosphorylated retinoblastoma protein (pRb) leading to maintenance of pRb-mediated cell cycle control. 4 As a result of truncation studies, we located the pRb-binding activity of RBP2-H1 to its C-term, containing a homolog region of the non-T/E1A-pRb binding domain known from other retinoblastoma binding proteins like RBP2. 5 Moreover, RBP2-H1 and its splicing variants PLU-1 and RBBP2H1a contain further well-conserved domains known to be involved in direct gene regulation and chromatin homeostasis, e.g. 3 PHD motifs and the ARID (AT-rich interacting) DNA-binding domain. [6][7][8][9] Although the 3 splicing variants show a cDNA sequence homology of more than 98%, RBP2-H1 differs from PLU-1 and RBBP2H1a by an additional exon encoding a region with strong homology to chromosomal ALU repeats. Thus, previously reported differences in tissue expression (PLU-1 shows a restricted expre...

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The X-Linked Mental Retardation Gene SMCX/JARID1C Defines a Family of Histone H3 Lysine 4 Demethylases

Cited by 623 publications

References 49 publications

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

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