Lsh Participates in DNA Methylation and Silencing of Stem Cell Genes

Xi, Sichuan; Geiman, Theresa M.; Briones, Victorino; Tao, Yong; Xu, Hong Ji; Muegge, Kathrin

doi:10.1002/stem.183

Cited by 59 publications

(71 citation statements)

References 58 publications

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“…Genomic DNA was sonicated to produce fragments ranging in size from 300 to 1000 bp. Five micrograms of fragmented DNA was used for a standard MeDIP assay (29,67) and precipitated with 10 μl monoclonal antibody against 5-methylcytidine (Eurogentec) followed by incubation with protein A agarose beads. DNA was recovered by phenolchloroform extraction followed by ethanol precipitation.…”

Section: Discussionmentioning

confidence: 99%

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Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Xu²,

Shan³

et al. 2013

J. Clin. Invest.

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124

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MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxyazacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy.

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Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was subjected to bisulfite treatment using QIAGEN Epifect kit (QIAGEN). The PCR products were separated in agarose gels, purified, and subcloned as described (65,67). Primers for bisulfite sequencing are listed in Supplemental Table 1.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Xu²,

Shan³

et al. 2013

J. Clin. Invest.

Self Cite

124

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“…LSH may also serve as a recruitment factor for DNMTs as it interacts with DNMT3A and DNMT3B and, indirectly via DNMT3B, with DNMT1 and histone deacetylases HDAC1 and HDAC2 (Zhu et al 2006;Myant and Stancheva 2008). Experiments using episomal plasmids and ES cells differentiating in culture have shown that LSH is essential for de novo DNA methylation of exogenous sequences and pluripotency genes but is largely dispensable for maintenance of DNA methylation (Zhu et al 2006;Xi et al 2009). However, a knockdown of LSH in primary human fibroblasts leads to a progressive loss of DNA methylation from satellite 3 sequences and other repeats, indicating that apart from facilitating de novo DNA methylation, LSH may have a role in the maintenance of DNA methylation at repetitive sequences (Suzuki et al 2008).…”

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confidence: 99%

LSH and G9a/GLP complex are required for developmentally programmed DNA methylation

Myant¹,

Termanis²,

Sundaram³

et al. 2010

Genome Res.

115

127

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LSH, a member of the SNF2 family of chromatin remodeling ATPases encoded by the Hells gene, is essential for normal levels of DNA methylation in the mammalian genome. While the role of LSH in the methylation of repetitive DNA sequences is well characterized, its contribution to the regulation of DNA methylation and the expression of proteincoding genes has not been studied in detail. In this report we investigate genome-wide patterns of DNA methylation at gene promoters in Hells -/-mouse embryonic fibroblasts (MEFs). We find that in the absence of LSH, DNA methylation is lost or significantly reduced at~20% of all normally methylated promoter sequences. As a consequence, a large number of genes are misexpressed in Hells -/-MEFs. Comparison of Hells -/-MEFs with wild-type MEFs and embryonic stem (ES) cells suggests that LSH is important for de novo DNA methylation events that accompany the establishment and differentiation of embryonic lineage cells. We further show that the generation of normal DNA methylation patterns and stable gene silencing at specific promoters require cooperation between LSH and the G9a/GLP complex of histone methylases. At such loci, G9a recruitment is compromised when LSH is absent or greatly reduced. Taken together, our data suggest a mechanism whereby LSH promotes binding of DNA methyltransferases and the G9a/GLP complex to specific loci and facilitates developmentally programmed DNA methylation and stable gene silencing during lineage commitment and differentiation.

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“…There are some examples of transcription factors that regulate oct4 expression by modulating epigenetic processes. The Lsh/Dnmt3 complex induces DNA methylation, and the cdx2/brg1 complex induces chromosome remodeling and suppresses oct4 expression during ES cell differentiation and trophectoderm formation, respectively A B C Xi et al, 2009). In contrast, CARM1 enhances oct4 gene expression by binding to the PE of oct4 and modulating histone H3 R17/26 methylation (Wu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

NonO Binds to the CpG Island of oct4 Promoter and Functions as a Transcriptional Activator of oct4 Gene Expression

Park¹,

Lee²,

Hwang³

et al. 2013

Molecules and Cells

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Lsh Participates in DNA Methylation and Silencing of Stem Cell Genes

Cited by 59 publications

References 58 publications

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

LSH and G9a/GLP complex are required for developmentally programmed DNA methylation

NonO Binds to the CpG Island of oct4 Promoter and Functions as a Transcriptional Activator of oct4 Gene Expression

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