HOXB13 controls cell state through super-enhancers

Aspuria, Paul‐Joseph; Cheon, Dong‐Joo; Beach, Jessica A.; Recouvreux, María Sol; Walts, Ann E.; Karlan, Beth Y.; Oršulić, Sandra

doi:10.1016/j.yexcr.2020.112039

Cited by 9 publications

(8 citation statements)

References 63 publications

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“…Specifically, HOXB13 was the top TF associated with binding at sites within the human hypermethylated DMBs. Recently, HOXB13 has been found to control cell state through binding to super-enhancer regions, suggesting a novel regulatory function for cell-type specific hypermethylation(48). In addition to the common TFBS enriched by all cell-type specific blocks, endothelial-specific TFs were found to be enriched in the endothelial-cell hypomethylated blocks, including EWS, ERG, Fli1, ETV2/4, and SOX6 (see Figure 4e ).…”

Section: Resultsmentioning

confidence: 99%

“…To further explore what common function these identified regions may have in human and mouse development, we performed motif analysis using HOMER to see if there were commonly enriched transcription factor binding sites (TFBS) (41). MADS motifs bound by MEF2 transcription factors were significantly enriched in both human and mouse cell-type specific hypomethylated blocks (Figure 3e (48). In addition to the common TFBS enriched by all cell-type specific blocks, endothelial-specific TFs were found to be enriched in the endothelial-cell hypomethylated blocks, including EWS, ERG, Fli1, ETV2/4, and SOX6 (see Figure 4e).…”

Section: Cell-type Specific Dna Blocks Are Mostly Hypomethylated and ...mentioning

confidence: 99%

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Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Barefoot

Loyfer

Kiliti

et al. 2022

Preprint

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Radiation therapy is an effective cancer treatment although damage to healthy tissues is common. Here we establish sequencing-based, cell-type specific DNA methylation reference maps of human and mouse tissues to infer the origins of cell-free DNA fragments released from dying cells into the circulation. We find cell-type specific DNA blocks mostly hypomethylated and located within genes intrinsic to cellular identity. In a mouse model, thoracic radiation-induced tissue damages were reflected by dose-dependent increases in lung endothelial, cardiomyocyte and hepatocyte methylated DNA in serum. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation indicating the impact on liver tissues. Thus, cell-free methylated DNA in serum can uncover cell-type specific effects of radiation on healthy tissues and inform treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Cell-type Specific Dna Blocks Are Mostly Hypomethylated and ...mentioning

confidence: 99%

Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Barefoot

Loyfer

Kiliti

et al. 2022

Preprint

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“…High HOXB13 expression is associated with poor survival rates for patients with glioblastoma, which may be due to the upregulation of long noncoding RNA HOXC-AS3 transcription [ 63 ]. In malignant striated muscle tumors, HOXB13 plays a role in promoting cancer by interfering with the differentiation of mesenchymal stem cells [ 64 ]. Previous research found HOXB13 was upregulated in LSCC [ 52 ], which is consistent with the findings of this study via SMD calculation.…”

Section: Discussionmentioning

confidence: 99%

The underlying molecular mechanism and identification of transcription factor markers for laryngeal squamous cell carcinoma

Mo¹,

Huang

et al. 2021

Bioengineered

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The screening and treatment of laryngeal squamous cell carcinoma (LSCC) still perplexes clinicians, making it necessary to explore new markers. To this end, this research examined the underlying molecular mechanism of LSCC based on high-throughput datasets ( n = 249) from multiple databases. It also identified transcription factors (TFs) independently associated with LSCC prognosis. Through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, differential expression genes of LSCC were deemed relevant to the extracellular matrix and its related structures or pathways, suggesting that the extracellular matrix plays an important role in LSCC. At the same time, several hub genes that may also have important roles in LSCC were identified via protein–protein interaction analysis, including CDC45, TPX2, AURKA, KIF2C, NUF, MUC1, MUC7, MUC4, MUC15, and MUC21 . Eight unreported LSCC prognostic TFs – BCAT1, CHD4, FOXA2, GATA6, HNF1A, HOXB13, MAFF, and TCF4 – were screened via Kaplan–Meier curves. Cox analysis determined for the first time that HOXB13 expression and gender were independently associated with LSCC prognosis. Compared to control tissues, elevated expression of HOXB13 was found in LSCC tissues (standardized mean difference = 0.44, 95% confidence interval [0.13–0.76]). HOXB13 expression also makes it feasible to screen LSCC from non-LSCC (area under the curve = 0.77), and HOXB13 may play an essential role in LSCC by regulating HOXB7 . In conclusion, HOXB13 may be a novel marker for LSCC clinical screening and treatment.

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“…HOXB13 has been considered to be a prognostic indicator for prostate cancer as it is found to be mutated in families with an increased risk of early-onset hereditary prostate cancer (34). The function of HOXB13 in a variety of diseases has been reported in recent years (8). It has been shown that HOXB13 contributes to the maturation and proliferation of infant cardiomyocytes (35).…”

Section: Discussionmentioning

confidence: 99%

“…Homeobox B13 (HOXB13) belongs to the homeobox family and is a master regulator in cell identity, differentiation, proliferation and migration during embryonic development, tumorigenesis and inflammatory reactions ( 7 , 8 ). In particular, homeobox genes are involved in vasculogenesis and vascular remodeling, which are common events during neointimal lesion formation in atherosclerosis and post-angioplasty restenosis ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

A microRNA‑17‑5p/homeobox B13 axis participates in the phenotypic modulation of vascular smooth muscle cells

Wang

Kuang

et al. 2021

Mol Med Rep

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Vascular smooth muscle cells (VSMCs) serve a decisive role in intimal hyperplasia, a common pathophysiological process that leads to numerous vascular disorders. The present study aimed to investigate the unknown mechanisms underlying VSMC phenotypic modulation and identified a novel microRNA (miRNA/miR)-17-5p/homeobox B13 (HOXB13) axis involved in the phenotypic switching, proliferation and migration of VSMCs. VSMCs were isolated from the thoracic aorta of Sprague-Dawley rats, cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay, cell migration was examined by Transwell migration assay and gene expression was detected using reverse transcription-quantitative PCR and western blot analyses. It was firstly found that incubation with platelet-derived growth factor-BB (PDGF-BB) recombinant protein resulted in a significant increase in HOXB13 expression in VSMCs. Using multiple miRNA prediction tools, miR-17-5p was identified as a potential regulator for HOXB13, since it had a 7-base perfect binding site and a 5-base imperfect binding site with the 3'-untranslated region of HOXB13 mRNA, and these sequences were highly conserved across species. The regulatory effect of miR-17-5p on HOXB13 was validated using luciferase reporter assays. The expression level of miR-17-5p was increased in VSMCs under PDGF-BB stimulation, and was negatively correlated with HOXB13 mRNA and protein expression. Moreover, the miR-17-5p mimics significantly inhibited the proliferation and migration of VSMCs, while antagomiR-17-5p showed the opposite effects, which could be abolished by HOXB13 knockdown. The miR-17-5p/HOXB13 axis also regulated the expression levels of the markers of differentiated VSMCs (α-smooth muscle actin, transgelin and smoothelin), proliferating cell nuclear antigen and cell migration proteins, including MMP-2 and -9. In conclusion, the present study demonstrated that miR-17-5p inhibited the phenotypic modulation VSMCs stimulated by PDGF-BB by downregulating HOXB13, indicating that these factors may be potential therapeutic targets for intimal hyperplasia.

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HOXB13 controls cell state through super-enhancers

Cited by 9 publications

References 63 publications

Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

The underlying molecular mechanism and identification of transcription factor markers for laryngeal squamous cell carcinoma

A microRNA‑17‑5p/homeobox B13 axis participates in the phenotypic modulation of vascular smooth muscle cells

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