The ATP binding site of the chromatin remodeling homolog Lsh is required for nucleosome density and <i>de novo</i> DNA methylation at repeat sequences

Ren, Jianke; Briones, Victorino; Barbour, Samantha; Yu, Weishi; Han, Yingbo; Terashima, Minoru; Muegge, Kathrin

doi:10.1093/nar/gku1371

Cited by 72 publications

(82 citation statements)

References 68 publications

(99 reference statements)

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“…LSH may repress the fh promoter independent of DNA methylation. LSH can increase nucleosome density (32), cause RNA polymerase II stalling (42,43), or promote gene silencing via a G9a/GLP complex during differentiation and early development (8). Here, we provide evidence for an interaction of LSH with G9a, recruitment of G9a to the fh promoter in a LSH-dependent manner, and subsequent chromatin modification leading to FH promoter repression, thus linking epigenetic regulation by LSH with suppression of the emerging tumor suppressor gene FH (21,44,45).…”

Section: Discussionmentioning

confidence: 67%

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Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Yan

Liu

et al. 2016

Cancer Research

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Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates a-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKa-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT.

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Section: Discussionmentioning

confidence: 67%

“…LSH is critical for chromatin function and establishment of DNA methylation (6,7,32,39). Reports show that LSH contributes to the malignant progression of prostate cancer, melanoma, head and neck cancer, etc.…”

Section: Discussionmentioning

confidence: 99%

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Yan

Liu

et al. 2016

Cancer Research

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“…Lymphoid-specific helicase (LSH) acts a chromatin modifier in DNA methylation 41, depletion of LSH increases DNA hypomethylation in 5-mC in repeats and somatic genes, leading to transcribed satellites repeat expression 42, 43. Alterations in DNA methylation, including the  hypomethylation of oncogenes and the hypermethylation of tumor suppressor genes, indicate that DNA methylation plays an important role in tumorigenesis including gliomas 7, 44, 45.…”

Section: Discussionmentioning

confidence: 99%

Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas

et al. 2017

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The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3β (GSK-3β), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3β increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3β signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3β/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma.

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“…Five animals were pooled for each experimental group. Bisulfite conversion of genomic DNA was performed using Bisulfite Conversion Kit (Active Motif), as described previously 65 . To monitor DNA methylation level of each ICR, the converted DNA was amplified under each PCR condition.…”

Section: Bisulfite Sequencingmentioning

confidence: 99%

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

et al. 2015

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Several studies have described phenotypic changes in the offspring of mice exposed to a variety of environmental factors, including diet, toxins, and stress; however, the molecular pathways involved in these changes remain unclear. Using a high fat diet (HFD)-induced obesity mouse model, we examined liver gene expression in male offspring and analyzed chromatin of paternal spermatozoa. We found that the hepatic mRNA level of 7 genes (out of 20 evaluated) was significantly altered in HFD male offspring compared to control mice, suggesting that phenotypic changes in the offspring depend on parental diet. We examined 7 imprinted loci in spermatozoa DNA from HFD-treated and control fathers by bisulfite sequencing, but did not detect changes in DNA methylation associated with HFD. Using chromatin immunoprecipitation followed by high-throughput sequencing, we found differential histone H3-occupancy at genes involved in the regulation of embryogenesis and differential H3K4me1-enrichment at transcription regulatory genes in HFD fathers vs. control mice. These results suggest that dietary exposure can modulate histone composition at regulatory genes implicated in developmental processes.

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The ATP binding site of the chromatin remodeling homolog Lsh is required for nucleosome density and de novo DNA methylation at repeat sequences

Cited by 72 publications

References 68 publications

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

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