Global Histone H3 Lysine 4 Trimethylation (H3K4me3) Landscape Changes in Response to TGFβ

Naik, Ankit; Dalpatraj, Nidhi; Thakur, Noopur

doi:10.1177/25168657211051755

Cited by 4 publications

(3 citation statements)

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“…Non-coding RNAs and epigenetic changes are also primarily involved in the regulation of gene expression. Interestingly, while the long non-coding RNA TUG1 facilitates the synthesis of LRG1 in ovarian cancer cells [ 35 ], TGFβ has been recently shown to induce histone H3 lysine 4 (H3K4) trimethylation and subsequent transcription of Lrg1 and other genes of the TGFβ superfamily in prostate cancer cells, pointing towards the establishment of a positive feedback loop and supporting the theory that LRG1 modulates the TGFβ axis in cancer [ 36 ] (Fig. 4 ).…”

Section: Reviewmentioning

confidence: 75%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

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Section: Reviewmentioning

confidence: 75%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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“…ChIP protocol was followed as mentioned in our published article. 35 The Illumina HiSeq × platform was used to sequence the ChIP-DNA samples. The essential details of the ChIP-Seq run and sequencing output are listed in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Global Gene Expression Regulation Mediated by TGFβ Through H3K9me3 Mark

2022

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Background: Epigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor beta (TGFβ) are important regulators of tumorigenesis. Our understanding of the interplay between the epigenetic bases of tumorigenesis and growth factor signaling in tumorigenesis is rudimentary. Some studies suggest a link between TGFβ signaling and the heterochromatinizing histone mark H3K9me3. There is evidence for signal-dependent interactions between R-Smads and histone methyltransferases. However, the effects of TGFβ signaling on genome wide H3K9me3 landscape remains unknown. Our research examines TGFβ -induced genome-wide H3K9me3 in prostate cancer. Method: Chromatin-Immunoprecipitation followed by sequencing was performed to analyze genome-wide association of H3K9me3 epigenetic mark. DAVID Functional annotation tool was utilized to understand the involvement of different Biological Processes and Molecular Function. MEME-ChIP tool was also used to analyze known and novel DNA-binding motifs. Results: H3K9me3 occupancy appears to increase at intronic regions after short-term (6 hours) TGFβ stimulation and at distal intergenic regions during long-term stimulation (24 hours). We also found evidence for a possible association of SLC transporters with H3K9me3 mark in presence of TGFβ during tumorigenesis. No direct correlation was found between the occupancy of H3K9me3 mark and the expression of various genes. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites. Conclusion: Our results point toward a positive association of oncogenic function of TGFβ and the H3K9me3 mark and provide a context to the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3.

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“…The study exhibited that SNAIL could demethylate H3K4me2 at E-cadherin promoter leading to down-regulated E-cadherin (66). Furthermore, previous studies suggested that genes associated with H3K4me3 were identified during EMT process in prostate cells and activation of H3K4me3 promoted TGF-ꞵ-induced EMT leading to tumorigenesis and progression in prostate cancer cells (133,134). However, the protein expression of genes associated with SMAD signaling was not evaluated in this study.…”

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confidence: 73%

Epigenetic regulation of reactive oxygen species-induced tumor progression in hepatocellular carcinoma

Phoyen

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Oxidative stress is a consequence of an imbalance of antioxidants and reactive species. The most common form of reactive species is derived from oxygen, called reactive oxygen species (ROS). ROS involve in pathogenesis of several diseases including cancers. Cancer genesis and progression are contributed through both genetic and epigenetic mechanisms. Histone modification, a post-translational modification at histone tails, is one of the epigenetic mechanisms known to participate in carcinogenesis and tumor progression. Although the ROS-induced histone modification alteration has been demonstrated in some cancers, the change in histone methylation and gene expression by ROS in hepatocellular carcinoma (HCC) is scarcely reported. This study aimed to investigate the effect of ROS on tumor progression via histone modification in HCC cell lines. Expression of inactive chromatin (H4K20me3, H3K9me3) and active chromatin (H3K4me3) marks and their clinical significance were also investigated. The result showed that ROS promoted epithelial-mesenchymal transition (EMT) in HCC cells, indicated by reduced expression of E-cadherin, and enhanced expression of ?-SMA and SNAIL. Cell migration, invasion, and colony formation were higher in HCC cells treated with ROS than the untreated controls. Co-treatment with antioxidant attenuated oxidative stress, inhibited EMT and decreased tumor progressivity in HCC cells exposed to H2O2. H4K20me3, H3K9me3, H3K4me3 and histone methyltransferases (SUV420H2, SUV39H1 and SMYD3) was upregulated in H2O2-treated HCC cells compared with the untreated controls. Chromatin immunoprecipitation-sequencing demonstrated that alteration of histone methylation (H4K20me3 and H3K4me3) by ROS was associated with upregulation of genes involved in DNA repair pathway (MRE11, BRCA1, MMS22L and RBBP8,) telomere maintenance (DCLRE1B, TERF1 and TERF2), and EMT pathway (SOS1 and RHOA) in HCC cells. The transcript expression of MRE11, BRCA1, MMS22L, RBBP8, DCLRE1B, TERF1 and TERF2 in HCC cells were increased following the H2O2 treatment. RBBP8 was selected to validate in the human HCC tissues, and it was overexpressed in the HCC tissues compared with the non-cancerous liver tissues. Expression of H4K20me3 was also higher in HCC tissues than the non-cancerous tissues. Elevated expression of H4K20me3 was associated with tumor recurrence and poor survival in HCC patients. In conclusion, ROS-induced oxidative stress promoted HCC progression through chromatin remodeling that subsequently upregulated genes related to EMT and DNA repairing pathways. H4K20me3 was upregulated in the HCC tissues, and its overexpression was clinically associated with the poor prognosis. The findings suggested that histone methylation, specifically H4K20me3, might be a promising marker for HCC prognosis, and it could be a target for development of HCC therapeutic agent in the future.

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Global Histone H3 Lysine 4 Trimethylation (H3K4me3) Landscape Changes in Response to TGFβ

Cited by 4 publications

References 61 publications

LRG1: an emerging player in disease pathogenesis

LRG1: an emerging player in disease pathogenesis

Global Gene Expression Regulation Mediated by TGFβ Through H3K9me3 Mark

Epigenetic regulation of reactive oxygen species-induced tumor progression in hepatocellular carcinoma

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