Lsh controls Hox gene silencing during development

Xi, Sichuan; Zhu, Haoshen; Xu, Hong Ji; Schmidtmann, Anja; Geiman, Theresa M.; Muegge, Kathrin

doi:10.1073/pnas.0703669104

Cited by 68 publications

(101 citation statements)

References 27 publications

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“…Indeed, Hoxa10-13 expression has been linked to the establishment of the thoracic and lumbar vertebrae identity (33). Likewise, a recent study highlighted the implication of LSH protein in the control of DNA methylation and silencing of other Hox genes, Hoxa5-7, during development (41). Therefore, although it may implicate distinct coregulatory factors at different stages of development, DNA methylation is likely to participate in the spatiotemporal regulation of homeotic genes.…”

Section: Discussionmentioning

confidence: 99%

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Velasco

Hubé

Rollin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

121

122

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Methylation of cytosine residues within the CpG dinucleotide in mammalian cells is an important mediator of gene expression, genome stability, X-chromosome inactivation, genomic imprinting, chromatin structure, and embryonic development. The majority of CpG sites in mammalian cells is methylated in a nonrandom fashion, raising the question of how DNA methylation is distributed along the genome. Here, we focused on the functions of DNA methyltransferase-3b (Dnmt3b), of which deregulated activity is linked to several human pathologies. We generated Dnmt3b hypomorphic mutant mice with reduced catalytic activity, which first revealed a deregulation of Hox genes expression, consistent with the observed homeotic transformations of the posterior axis. In addition, analysis of deregulated expression programs in Dnmt3b mutant embryos, using DNA microarrays, highlighted illegitimate activation of several germ-line genes in somatic tissues that appeared to be linked directly to their hypomethylation in mutant embryos. We provide evidence that these genes are direct targets of Dnmt3b. Moreover, the recruitment of Dnmt3b to their proximal promoter is dependant on the binding of the E2F6 transcriptional repressor, which emerges as a common hallmark in the promoters of genes found to be up-regulated as a consequence of impaired Dnmt3b activity. Therefore, our results unraveled a coordinated regulation of genes involved in meiosis, through E2F6-dependant methylation and transcriptional silencing in somatic tissues.DNA methylation | immunodeficiency | centromeric instability | facial anomalies | E2F family | hypomorphic mutation | hox genes

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Section: Discussionmentioning

confidence: 99%

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Velasco

Hubé

Rollin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

121

122

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“…It has previously been shown that repression of Hox genes and other key developmental regulators is established in embryonic stem (ES) cells (Boyer et al, 2006). Thus, we used murine ES cells to perform chromatin immunoprecipitation on four genes, HoxA7, HoxA10, HoxA11, and Arf, which have previously been shown to be directly regulated by Bmi1 (Cao et al, 2005;Bracken et al, 2007;Kotake et al, 2007;Xi et al, 2007). We found that Bmi1 was directly bound to the promoters of HoxA7, HoxA10, HoxAll, and Arf in mouse embryonic stem cells (Fig.…”

Section: Bmi1 and E2f6 Synergize In Axial Skeleton Development And Comentioning

confidence: 94%

E2f6 and Bmi1 cooperate in axial skeletal development

Courel

Friesenhahn

Lees

2008

Developmental Dynamics

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Bmi1 is a Polycomb Group protein that functions as a component of Polycomb Repressive Complex 1 (PRC1)to control axial skeleton development through Hox gene repression. Bmi1 also represses transcription of the Ink4a-Arf locus and is consequently required to maintain the proliferative and self-renewal properties of hematopoietic and neural stem cells. Previously, one E2F family member, E2F6, has been shown to interact with Bmi1 and other known PRC1 components. However, the biological relevance of this interaction is unknown. In this study, we use mouse models to investigate the interplay between E2F6 and Bmi1. This analysis shows that E2f6 and Bmi1 cooperate in the regulation of Hox genes, and consequently axial skeleton development, but not in the repression of the Ink4a-Arf locus. These findings underscore the significance of the E2F6 -Bmi1 interaction in vivo and suggest that the Hox and Ink4a-Arf loci are regulated by somewhat different mechanisms.

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“…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.

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125

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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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Lsh controls Hox gene silencing during development

Cited by 68 publications

References 27 publications

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

E2f6 and Bmi1 cooperate in axial skeletal development

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

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