Polycomb Repressive Complexes in <i>Hox</i> Gene Regulation: Silencing and Beyond

Gentile, Claudia; Kmita, Marie

doi:10.1002/bies.201900249

Cited by 28 publications

(12 citation statements)

References 131 publications

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“…Hox proteins specify development of body segments of organisms and are pivotal for normal healthy development. Their expression is regulated by polycomb repressive complex 43 , whose DNA targets are consistently identified, as well in this study, as being increasingly methylated with age. Hence the involvement of HOX loci further consolidates the importance of the process of development in aging.…”

Section: Discussionsupporting

confidence: 73%

Pan-primate DNA methylation clocks

Horvath

Haghani

Zoller

et al. 2020

Preprint

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DNA methylation data have been successfully used to develop highly accurate estimators of age (“epigenetic clocks”) in several mammalian species. With a view of extending epigenetic clocks to primates, we analyzed DNA methylation profiles from five primate species; Papio hamadryas (baboons), Callithrix jacchus (common marmoset), Chlorocebus sabaeus (vervet monkey), Macaca mulatta (rhesus macaque), and Homo sapiens (human). From these we present here, a highly accurate primate epigenetic clock. This clock is based on methylation profiles of CpGs that are highly conserved and are located on a custom methylation array (HorvathMammalMethylChip40). Furthermore, we carried out in-depth analysis of the baboon, as it is evolutionarily the closest primate to humans that can be employed in biomedical research. We present five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. To facilitate translational capability, we constructed two dual-species, human-baboon clocks, whereby one measures ages of both species in units of years, while the other reports ages relative to the maximum lifespan of the species. Although the primate clock applies to all five primate species, the baboon-specific clocks exhibit only moderate age correlations with other primates. We also provide detailed gene and pathway analyses of individual CpGs that relate to age and sex across different primate species. Ten out of 739 sex related CpGs in primate species are located near 9 autosomal genes (including FAM217A, CDYL, POU3F2, and UHRF2). Overall, this study sheds light on epigenetic aging mechanisms in primates, and the potential influence of sex.

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Section: Discussionsupporting

confidence: 73%

Pan-primate DNA methylation clocks

Horvath

Haghani

Zoller

et al. 2020

Preprint

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“…In addition, HOX genes exert their function by regulating cell proliferation and differentiation during embryogenesis and organogenesis [35] . Many HOX genes display altered expression patterns in a variety of tumors.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between NSPc1 and DNA methylation represses HOXA11 expression and promotes apoptosis of trophoblast cells during preeclampsia

Jiang¹,

Xie²,

Ding³

et al. 2023

ABBS

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Accumulating evidence has shown that the apoptosis of trophoblast cells plays an important role in the pathogenesis of preeclampsia, and an intricate interplay between DNA methylation and polycomb group (PcG) protein-mediated gene silencing has been highlighted recently. Here, we provide evidence that the expression of nervous system polycomb 1 (NSPc1), a BMI1 homologous polycomb protein, is significantly elevated in trophoblast cells during preeclampsia, which accelerates trophoblast cell apoptosis. Since NSPc1 acts predominantly as a transcriptional inactivator that specifically represses HOXA11 expression in trophoblast cells during preeclampsia, we further show that NSPc1 is required for DNMT3a recruitment and maintenance of the DNA methylation in the HOXA11 promoter in trophoblast cells during preeclampsia. In addition, we find that the interplay of DNMT3a and NSPc1 represses the expression of HOXA11 and promotes trophoblast cell apoptosis. Taken together, these results indicate that the cooperation between NSPc1 and DNMT3a reduces HOXA11 expression in preeclampsia pathophysiology, which provides novel therapeutic approaches for targeted inhibition of trophoblast cell apoptosis during preeclampsia pathogenesis.

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“…Considering that DNA methylation differences between H3K27M DMGs and H3-WT tumours involve homeobox genes with functions related to regulation and development suggests that H3K27M DMGs and H3-WT tumours may arise from different cell lineages or through blocks of alternate differentiation pathways. Interestingly, dysregulation of homeobox genes have previously been described in adult GBMs 40 , and more recently in H3.3 G34-mutant gliomas where dysregulated high expression of GSX2 and DLX1/2 reflects the stalled development of the tumour in an interneuron progenitor state 41 www.nature.com/scientificreports/ preference of PRC2 binding and repression of genes involved in regulation of development and cell fate, including HOX and TLX genes [42][43][44] . EZHIP binds to the active site of the SET domain of EZH2 within the PRC2 complex 12 , thus, it is plausible that within the H3-WT cohort, binding of EZHIP to the PRC2 complex leads to differential DNA methylation of the homeobox genes observed.…”

Section: Discussionmentioning

confidence: 99%

Histone H3-wild type diffuse midline gliomas with H3K27me3 loss are a distinct entity with exclusive EGFR or ACVR1 mutation and differential methylation of homeobox genes

Ajuyah

Mayoh

Lau

et al. 2023

Sci Rep

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Diffuse midline gliomas (DMG) harbouring H3K27M mutation are paediatric tumours with a dismal outcome. Recently, a new subtype of midline gliomas has been described with similar features to DMG, including loss of H3K27 trimethylation, but lacking the canonical H3K27M mutation (H3-WT). Here, we report a cohort of five H3-WT tumours profiled by whole-genome sequencing, RNA sequencing and DNA methylation profiling and combine their analysis with previously published cases. We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation. Affected patients share a similar poor prognosis as patients with H3K27M DMG. Global molecular analysis of H3-WT and H3K27M DMG reveal distinct transcriptome and methylome profiles including differential methylation of homeobox genes involved in development and cellular differentiation. Patients have distinct clinical features, with a trend demonstrating ACVR1 mutations occurring in H3-WT tumours at an older age. This in-depth exploration of H3-WT tumours further characterises this novel DMG, H3K27-altered sub-group, characterised by a specific immunohistochemistry profile with H3K27me3 loss, wild-type H3K27M and positive EZHIP. It also gives new insights into the possible mechanism and pathway regulation in these tumours, potentially opening new therapeutic avenues for these tumours which have no known effective treatment. This study has been retrospectively registered on clinicaltrial.gov on 8 November 2017 under the registration number NCT03336931 (https://clinicaltrials.gov/ct2/show/NCT03336931).

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Polycomb Repressive Complexes in Hox Gene Regulation: Silencing and Beyond

Cited by 28 publications

References 131 publications

Pan-primate DNA methylation clocks

Pan-primate DNA methylation clocks

Cooperation between NSPc1 and DNA methylation represses HOXA11 expression and promotes apoptosis of trophoblast cells during preeclampsia

Histone H3-wild type diffuse midline gliomas with H3K27me3 loss are a distinct entity with exclusive EGFR or ACVR1 mutation and differential methylation of homeobox genes

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