Epigenetic mechanisms and boundaries in the regulation of mammalian Hox clusters

Srivastava, Surabhi; Dhawan, Jyotsna; Mishra, Rakesh

doi:10.1016/j.mod.2015.07.015

Cited by 10 publications

(6 citation statements)

References 105 publications

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“…The expression of HOX genes is tightly regulated by epigenetic mechanisms during normal development and cancer ( 20 , 21 ). Since the HOXB cluster genes were generally upregulated as a whole in MCF7-TAMR cells, we expected that different epigenetic states can be generated in the HOXB locus during the transition to acquired TAM resistance.…”

Section: Resultsmentioning

confidence: 99%

Up-regulation ofHOXBcluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells

et al. 2018

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Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

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Section: Resultsmentioning

confidence: 99%

Up-regulation ofHOXBcluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells

et al. 2018

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“…In line with this study, our results showing a differential expression in microvessels of distinct vascular beds sustain the possibility that Hox genes, known as master regulators of positional identity, can define endothelial phenotypes. It is tempting to speculate that upstream epigenetic events, which are known to regulate Hox gene expression [27], are responsible for these different endothelial phenotypes. Indeed, Hox gene expression during development undergoes tight spatiotemporal regulation, partly by chromatin structure and epigenetic factors [28].…”

Section: Resultsmentioning

confidence: 99%

Gene expression comparison reveals distinct basal expression of HOX members and differential TNF-induced response between brain- and spinal cord-derived microvascular endothelial cells

Molino¹,

Jabès²,

Bonnet

et al. 2016

J Neuroinflammation

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BackgroundThe heterogeneity of endothelial cell types underlies their remarkable ability to sub-specialize and provide specific requirements for a given vascular bed. Here, we compared rat microvascular endothelial cells (MECs) derived from the brain and spinal cord in both basal and inflammatory conditions.MethodsWe used whole rat genome microarrays to compare, at different time points, basal and TNF-α-induced gene expression of rat MECs from in vitro models of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). Validation at both messenger RNA (mRNA) and protein levels was performed on freshly extracted microvessels (MVs) from the brain and spinal cord (BMVs and SCMVs, respectively), as these were considered the closest in vivo tissues to cultured MECs.ResultsMost of the genes encoding adhesion/tight junction molecules and known endothelial markers were similarly expressed in brain and spinal cord MECs (BMECs and SCMECs, respectively). However, one striking finding was the higher expression of several Hox genes, which encode transcription factors involved in positional identity. The differential expression of Hoxa9 and Hoxb7 at the mRNA levels as well as protein levels was confirmed in BMVs and SCMVs. Although the TNF-α response was in general higher in BMECs than in SCMECs at 12 h, the opposite was observed at 48 h. Furthermore, we found that expression of Tnfrsf1a and Tnfrsf1b encoding the TNF receptor super-family member 1a/TNFR1 and 1b/TNFR2, respectively, were constitutively higher in BMVs compared to SCMVs. However, only Tnfrsf1b was induced in SCMECs in response to TNF-α at 24 and 48 h.ConclusionsOur results support a role for HOX members in defining the positional identities of MECs in vivo. Our data also suggest that the delayed transcriptional activation upon TNF-α treatment in SCMECs results from the requirement of the TNF-induced expression of Tnfrsf1b. In contrast, its high basal expression in BMECs might be sufficient to confer an immediate and efficient TNF-α response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0749-6) contains supplementary material, which is available to authorized users.

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“…Gene expression regulation is typically accompanied by an altered occupancy of active and inactive histone marks on gene promoters [66, 67]. The active state of the HOXA gene cluster is marked by active histone marks such as H3K9ac and H3K4me3, while the inactive state shows an enrichment of inactive marks such as H3K9me3 and H3K27me3 [36, 66, 68]. For instance, histone deacetylases and PRC2 complex proteins modify levels of active and inactive histone marks on the HOXA gene cluster in NT2/D1 embryonal carcinoma cells [38].…”

Section: Discussionmentioning

confidence: 99%

HOXA repression is mediated by nucleoporin Nup93 assisted by its interactors Nup188 and Nup205

Labade

Karmodiya

Sengupta

2016

Epigenetics & Chromatin

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BackgroundThe nuclear pore complex (NPC) mediates nuclear transport of RNA and proteins into and out of the nucleus. Certain nucleoporins have additional functions in chromatin organization and transcription regulation. Nup93 is a scaffold nucleoporin at the nuclear pore complex which is associated with human chromosomes 5, 7 and 16 and with the promoters of the HOXA gene as revealed by ChIP-on-chip studies using tiling microarrays for these chromosomes. However, the functional consequences of the association of Nup93 with HOXA is unknown.ResultsHere, we examined the association of Nup93 with the HOXA gene cluster and its consequences on HOXA gene expression in diploid colorectal cancer cells (DLD1). Nup93 showed a specific enrichment ~1 Kb upstream of the transcription start site of each of the HOXA1, HOXA3 and HOXA5 promoters, respectively. Furthermore, the association of Nup93 with HOXA was assisted by its interacting partners Nup188 and Nup205. The depletion of the Nup93 sub-complex significantly upregulated HOXA gene expression levels. However, expression levels of a control gene locus (GLCCI1) on human chromosome 7 were unaffected. Three-dimensional fluorescence in situ hybridization (3D-FISH) analyses revealed that the depletion of the Nup93 sub-complex (but not Nup98) disengages the HOXA gene locus from the nuclear periphery, suggesting a potential role for Nup93 in tethering and repressing the HOXA gene cluster. Consistently, Nup93 knockdown increased active histone marks (H3K9ac), decreased repressive histone marks (H3K27me3) on the HOXA1 promoter and increased transcription elongation marks (H3K36me3) within the HOXA1 gene. Moreover, the combined depletion of Nup93 and CTCF (a known organizer of HOXA gene cluster) but not Nup93 alone, significantly increased GLCCI1 gene expression levels. Taken together, this suggests a novel role for Nup93 and its interactors in repressing the HOXA gene cluster.ConclusionsThis study reveals that the nucleoporin Nup93 assisted by its interactors Nup188 and Nup205 mediates the repression of HOXA gene expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0106-0) contains supplementary material, which is available to authorized users.

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Epigenetic mechanisms and boundaries in the regulation of mammalian Hox clusters

Cited by 10 publications

References 105 publications

Up-regulation ofHOXBcluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells

Up-regulation ofHOXBcluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells

Gene expression comparison reveals distinct basal expression of HOX members and differential TNF-induced response between brain- and spinal cord-derived microvascular endothelial cells

HOXA repression is mediated by nucleoporin Nup93 assisted by its interactors Nup188 and Nup205

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