Mechanisms Underlying Hox-Mediated Transcriptional Outcomes

Cain, Brittany; Gebelein, Brian

doi:10.3389/fcell.2021.787339

Cited by 14 publications

(9 citation statements)

References 90 publications

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“…HOX genes are involved in developmental processes [24] so they are not expressed in adult brain, but they are re-expressed in malignant gliomas and linked to tumorigenesis [25]. To produce gene-specific regulatory outcomes, interactions of HOX factors with other TFs (that are expressed in tissue- and cell type-specific manners) are required [26]. Expression of JUN was significantly up-regulated in GIV when compared to GII (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Roura

Szadkowska

Poleszak

et al. 2022

Preprint

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BackgroundGlioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite gross surgery and forceful radio- and chemotherapy, survival of GBM patients did not improve over decades. Several studies reported transcription deregulation in GBMs but regulatory mechanisms driving overexpression of GBM-specific genes remain largely unknown. Transcription in open chromatin regions is directed by transcription factors (TFs) that bind to specific motifs, recruit co-activators/repressors and the transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new and targetable mechanisms of gliomagenesis.ResultsWe predicted TFs-regulated networks in GBMs in silico and intersected them with putative TF binding sites identified in the accessible chromatin in human glioma cells and GBM patient samples. The Cancer Genome Atlas and Glioma Atlas datasets (DNA methylation, H3K27 acetylation, transcriptomic profiles) were explored to elucidate TFs-gene regulatory networks and effects of the epigenetic background. In contrast to the majority of tumors, c-Jun expression was higher in GBMs than in normal brain and c-Jun binding sites were found in multiple genes overexpressed in GBMs such as VIM, FOSL2 or UPP1. Binding of c-Jun to the VIM gene promoter is stronger in GBM cells than in cells derived from benign glioma as evidenced by gel shift and supershift assays. Regulatory regions of a majority of the c-Jun targets have distinct DNA methylation in GBMs suggesting the contribution of DNA methylation to the c-Jun-dependent regulation.ConclusionsWe identified distinct TFs-gene networks in GBMs compared to benign gliomas, a predominant role of c-Jun in controlling genes driving gliomagenesis and a modulatory role of DNA methylation.

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Section: Resultsmentioning

confidence: 99%

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Roura

Szadkowska

Poleszak

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…HOX genes are involved in developmental processes [ 24 ] so they are not expressed in the adult brain, but they are re-expressed in malignant gliomas and linked to tumorigenesis [ 25 ]. To exert gene-specific regulatory outcomes, HOX factors must interact with other TFs (that are expressed in a tissue- and cell type-specific manner) [ 26 ]. Expression of JUN was significantly up-regulated in GIV when compared to GII (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

et al. 2023

View full text Add to dashboard Cite

Background Glioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite extensive tumor resection followed by radio- and chemotherapy, life expectancy of GBM patients did not improve over decades. Several studies reported transcription deregulation in GBMs, but regulatory mechanisms driving overexpression of GBM-specific genes remain largely unknown. Transcription in open chromatin regions is directed by transcription factors (TFs) that bind to specific motifs, recruit co-activators/repressors and the transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new and targetable mechanisms of gliomagenesis. Results We predicted TFs-regulated networks in GBMs in silico and intersected them with putative TF binding sites identified in the accessible chromatin in human glioma cells and GBM patient samples. The Cancer Genome Atlas and Glioma Atlas datasets (DNA methylation, H3K27 acetylation, transcriptomic profiles) were explored to elucidate TFs-gene regulatory networks and effects of the epigenetic background. In contrast to the majority of tumors, c-Jun expression was higher in GBMs than in normal brain and c-Jun binding sites were found in multiple genes overexpressed in GBMs, including VIM, FOSL2 or UPP1. Binding of c-Jun to the VIM gene promoter was stronger in GBM-derived cells than in cells derived from benign glioma as evidenced by gel shift and supershift assays. Regulatory regions of the majority of c-Jun targets have distinct DNA methylation patterns in GBMs as compared to benign gliomas, suggesting the contribution of DNA methylation to the c-Jun-dependent gene expression. Conclusions GBM-specific TFs-gene networks identified in GBMs differ from regulatory pathways attributed to benign brain tumors and imply a decisive role of c-Jun in controlling genes that drive glioma growth and invasion as well as a modulatory role of DNA methylation.

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“…Since Abd-B was derepressed upon Ph depletion, increased Abd-B may modify the chromatin landscape to reduce chromatin accessibility around the mical locus, thereby inhibiting Mical expression. Alternatively, Hox proteins are major drivers of gene transcriptional repression [ 77 ]. Abd-B may associate with a transcriptional repressive complex to repress mical transcription and thereby inhibit dendrite pruning.…”

Section: Discussionmentioning

confidence: 99%

Polycomb group genes are required for neuronal pruning in Drosophila

Lau

Yong

et al. 2023

BMC Biol

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Background Pruning that selectively eliminates unnecessary or incorrect neurites is required for proper wiring of the mature nervous system. During Drosophila metamorphosis, dendritic arbourization sensory neurons (ddaCs) and mushroom body (MB) γ neurons can selectively prune their larval dendrites and/or axons in response to the steroid hormone ecdysone. An ecdysone-induced transcriptional cascade plays a key role in initiating neuronal pruning. However, how downstream components of ecdysone signalling are induced remains not entirely understood. Results Here, we identify that Scm, a component of Polycomb group (PcG) complexes, is required for dendrite pruning of ddaC neurons. We show that two PcG complexes, PRC1 and PRC2, are important for dendrite pruning. Interestingly, depletion of PRC1 strongly enhances ectopic expression of Abdominal B (Abd-B) and Sex combs reduced, whereas loss of PRC2 causes mild upregulation of Ultrabithorax and Abdominal A in ddaC neurons. Among these Hox genes, overexpression of Abd-B causes the most severe pruning defects, suggesting its dominant effect. Knockdown of the core PRC1 component Polyhomeotic (Ph) or Abd-B overexpression selectively downregulates Mical expression, thereby inhibiting ecdysone signalling. Finally, Ph is also required for axon pruning and Abd-B silencing in MB γ neurons, indicating a conserved function of PRC1 in two types of pruning. Conclusions This study demonstrates important roles of PcG and Hox genes in regulating ecdysone signalling and neuronal pruning in Drosophila. Moreover, our findings suggest a non-canonical and PRC2-independent role of PRC1 in Hox gene silencing during neuronal pruning.

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Mechanisms Underlying Hox-Mediated Transcriptional Outcomes

Cited by 14 publications

References 90 publications

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Polycomb group genes are required for neuronal pruning in Drosophila

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