International Journal of Molecular Sciences

Research

Jump to: Review

12 pages, 2664 KiB

Open AccessArticle

Conditional Loss of MEF2C Expression in Osteoclasts Leads to a Sex-Specific Osteopenic Phenotype

by Ravi Maisuria, Andrew Norton, Cynthia Shao, Elizabeth W. Bradley and Kim Mansky

Int. J. Mol. Sci. 2023, 24(16), 12686; https://doi.org/10.3390/ijms241612686 - 11 Aug 2023

Cited by 1 | Viewed by 1071

Abstract

Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that the reduced expression of MEF2C contributes to osteopetrosis and the dysregulation of pathological bone remodeling. Our current study aims [...] Read more.

Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that the reduced expression of MEF2C contributes to osteopetrosis and the dysregulation of pathological bone remodeling. Our current study aims to determine how MEF2C contributes to osteoclast differentiation and to analyze the skeletal phenotype of Mef2c-cKO mice (Cfms-cre; Mef2c^fl/fl). qRT-PCR and Western blot demonstrated that Mef2c expression is highest during the early days of osteoclast differentiation. Osteoclast genes, including c-Fos, c-Jun, Dc-stamp, Cathepsin K, and Nfatc1, had a significant reduction in expression, along with a reduction in osteoclast size. Despite reduced CTX activity, female Mef2c cKO mice were osteopenic, with decreased bone formation as determined via a P1NP ELISA, and a reduced number of osteoblasts. There was no difference between male WT and Mef2c-cKO mice. Our results suggest that Mef2c is critical for osteoclastogenesis, and that its dysregulation leads to a sex-specific osteopenic phenotype. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

13 pages, 1984 KiB

Open AccessCommunication

DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson’s Individuals with GBA1 Mutations

by Adam R. Smith, David M. Richards, Katie Lunnon, Anthony H. V. Schapira and Anna Migdalska-Richards

Int. J. Mol. Sci. 2023, 24(3), 2687; https://doi.org/10.3390/ijms24032687 - 31 Jan 2023

Cited by 3 | Viewed by 1645

Abstract

Parkinson’s disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi [...] Read more.

Parkinson’s disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

12 pages, 2967 KiB

Open AccessArticle

Urinary Measurement of Epigenetic DNA Modifications and 8-oxodG as Possible Noninvasive Markers of Colon Cancer Evolution

by Aleksandra Skalska-Bugala, Agnieszka Siomek-Gorecka, Zbigniew Banaszkiewicz, Ryszard Olinski and Rafal Rozalski

Int. J. Mol. Sci. 2022, 23(22), 13826; https://doi.org/10.3390/ijms232213826 - 10 Nov 2022

Cited by 2 | Viewed by 1211

Abstract

The active DNA demethylation mechanism involves 5-methylcytosine (5-mCyt) enzymatic oxidation with the subsequent formation of 5-hydroxymethylcytosine (5-hmCyt), which can be further oxidized to 5-formylcytosine (5-fCyt) and 5-carboxylcytosine (5-caCyt). The products of active DNA demethylation are released into the bloodstream and eventually also appear [...] Read more.

The active DNA demethylation mechanism involves 5-methylcytosine (5-mCyt) enzymatic oxidation with the subsequent formation of 5-hydroxymethylcytosine (5-hmCyt), which can be further oxidized to 5-formylcytosine (5-fCyt) and 5-carboxylcytosine (5-caCyt). The products of active DNA demethylation are released into the bloodstream and eventually also appear in urine. We used online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) to compare DNA methylation marks and 8-oxo-2′-deoxyguanosine (8-oxodG) in colorectal cancer and pre-cancerous condition in urine. The study included four groups of subjects: healthy controls, patients with inflammatory bowel disease (IBD), persons with adenomatous polyps (AD), and individuals with colorectal cancer (CRC). We have found that the level of 5-fCyt in urine was significantly lower for CRC and polyp groups than in the control group. The level of 5-hmCyt was significantly higher only in the CRC group compared to the control (2.3 vs. 2.1 nmol/mmol creatinine). Interestingly, we have found highly statistically significant correlation of 5-hydroxymethyluracil with 5-hydroxymethylcytosine, 5-(hydroxymethyl)-2′-deoxycytidine, 5-(hydroxymethyl)-2′-deoxyuridine, and 5-methyl-2′-deoxycytidine in the CRC patients’ group. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

20 pages, 2918 KiB

Open AccessArticle

The Significance of MGMT Promoter Methylation Status in Diffuse Glioma

by Nikola Jovanović, Milica Lazarević, Vladimir J. Cvetković, Vesna Nikolov, Jelena Kostić Perić, Milena Ugrin, Sonja Pavlović and Tatjana Mitrović

Int. J. Mol. Sci. 2022, 23(21), 13034; https://doi.org/10.3390/ijms232113034 - 27 Oct 2022

Cited by 2 | Viewed by 2021

Abstract

A single-institution observational study with 43 newly diagnosed diffuse gliomas defined the isocitrate dehydrogenase 1 and 2 (IDH1/2) gene mutation status and evaluated the prognostic relevance of the methylation status of the epigenetic marker O⁶-methylguanine-DNA methyltransferase (MGMT). [...] Read more.

A single-institution observational study with 43 newly diagnosed diffuse gliomas defined the isocitrate dehydrogenase 1 and 2 (IDH1/2) gene mutation status and evaluated the prognostic relevance of the methylation status of the epigenetic marker O⁶-methylguanine-DNA methyltransferase (MGMT). Younger patients (<50 years) with surgically resected glioma and temozolomide (TMZ) adjuvant chemotherapy were associated with better prognosis, consistent with other studies. The methylation status depends on the chosen method and the cut-off value determination. Methylation-specific PCR (MSP) established the methylation status for 36 glioma patients (19 (52.8%) positively methylated and 17 (47.2%) unmethylated) without relevancy for the overall survival (OS) (p = 0.33). On the other side, real-time methylation-specific PCR (qMSP) revealed 23 tumor samples (54%) that were positively methylated without association with OS (p = 0.15). A combined MSP analysis, which included the homogenous cohort of 24 patients (>50 years with surgical resection and IDH1/2-wildtype diffuse glioma), distinguished 10 (41.6%) methylated samples from 14 (58.4%) unmethylated samples. Finally, significant correlation between OS and methylation status was noticed (p ≈ 0.05). The OS of the hypermethylated group was 9.6 ± 1.77 months, whereas the OS of the unmethylated group was 5.43 ± 1.04 months. Our study recognized the MGMT promoter methylation status as a positive prognostic factor within the described homogenous cohort, although further verification in a larger population of diffuse gliomas is required. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

10 pages, 1037 KiB

Open AccessArticle

Methylome Profiling in Fabry Disease in Clinical Practice: A Proof of Concept

by Teodolinda Di Risi, Mariella Cuomo, Roberta Vinciguerra, Sara Ferraro, Rosa Della Monica, Davide Costabile, Michela Buonaiuto, Federica Trio, Ettore Capoluongo, Roberta Visconti, Eleonora Riccio, Antonio Pisani and Lorenzo Chiariotti

Int. J. Mol. Sci. 2022, 23(20), 12110; https://doi.org/10.3390/ijms232012110 - 11 Oct 2022

Cited by 3 | Viewed by 1294

Abstract

Anderson–Fabry disease (FD) is an X-linked disease caused by a functional deficit of the α-galactosidase A enzyme. FD diagnosis relies on the clinical manifestations and research of GLA gene mutations. However, because of the lack of a clear genotype/phenotype correlation, FD diagnosis can [...] Read more.

Anderson–Fabry disease (FD) is an X-linked disease caused by a functional deficit of the α-galactosidase A enzyme. FD diagnosis relies on the clinical manifestations and research of GLA gene mutations. However, because of the lack of a clear genotype/phenotype correlation, FD diagnosis can be challenging. Recently, several studies have highlighted the importance of investigating DNA methylation patterns for confirming the correct diagnosis of different rare Mendelian diseases, but to date, no such studies have been reported for FD. Thus, in the present investigation, we analyzed for the first time the genome-wide methylation profile of a well-characterized cohort of patients with Fabry disease. We profiled the methylation status of about 850,000 CpG sites in 5 FD patients, all carrying the same mutation in the GLA gene (exon 6 c.901C>G) and presenting comparable low levels of α-Gal A activity. We found that, although the whole methylome profile did not discriminate the FD group from the unaffected one, several genes were significantly differentially methylated in Fabry patients. Thus, we provide here a proof of concept, to be tested in patients with different mutations and in a larger cohort, that the methylation state of specific genes can potentially identify Fabry patients and possibly predict organ involvement and disease evolution. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

18 pages, 6246 KiB

Open AccessArticle

Epigenetic and Transcriptomic Programming of HSC Quiescence Signaling in Large for Gestational Age Neonates

by Alexandre Pelletier, Arnaud Carrier, Yongmei Zhao, Mickaël Canouil, Mehdi Derhourhi, Emmanuelle Durand, Lionel Berberian-Ferrato, John Greally, Francine Hughes, Philippe Froguel, Amélie Bonnefond and Fabien Delahaye

Int. J. Mol. Sci. 2022, 23(13), 7323; https://doi.org/10.3390/ijms23137323 - 30 Jun 2022

Cited by 3 | Viewed by 2768

Abstract

Excessive fetal growth is associated with DNA methylation alterations in human hematopoietic stem and progenitor cells (HSPC), but their functional impact remains elusive. We implemented an integrative analysis combining single-cell epigenomics, single-cell transcriptomics, and in vitro analyses to functionally link DNA methylation changes [...] Read more.

Excessive fetal growth is associated with DNA methylation alterations in human hematopoietic stem and progenitor cells (HSPC), but their functional impact remains elusive. We implemented an integrative analysis combining single-cell epigenomics, single-cell transcriptomics, and in vitro analyses to functionally link DNA methylation changes to putative alterations of HSPC functions. We showed in hematopoietic stem cells (HSC) from large for gestational age neonates that both DNA hypermethylation and chromatin rearrangements target a specific network of transcription factors known to sustain stem cell quiescence. In parallel, we found a decreased expression of key genes regulating HSC differentiation including EGR1, KLF2, SOCS3, and JUNB. Our functional analyses showed that this epigenetic programming was associated with a decreased ability for HSCs to remain quiescent. Taken together, our multimodal approach using single-cell (epi)genomics showed that human fetal overgrowth affects hematopoietic stem cells’ quiescence signaling via epigenetic programming. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

Review

Jump to: Research

19 pages, 1129 KiB

Open AccessReview

Epigenetic Factors Related to Low Back Pain: A Systematic Review of the Current Literature

by Alberto Ruffilli, Simona Neri, Marco Manzetti, Francesca Barile, Giovanni Viroli, Matteo Traversari, Elisa Assirelli, Fabio Vita, Giuseppe Geraci and Cesare Faldini

Int. J. Mol. Sci. 2023, 24(3), 1854; https://doi.org/10.3390/ijms24031854 - 17 Jan 2023

Cited by 5 | Viewed by 2600

Abstract

Low back pain (LBP) is one of the most common causes of pain and disability. At present, treatment and interventions for acute and chronic low back pain often fail to provide sufficient levels of pain relief, and full functional restoration can be challenging. [...] Read more.

Low back pain (LBP) is one of the most common causes of pain and disability. At present, treatment and interventions for acute and chronic low back pain often fail to provide sufficient levels of pain relief, and full functional restoration can be challenging. Considering the significant socio-economic burden and risk-to-benefit ratio of medical and surgical intervention in low back pain patients, the identification of reliable biomarkers such as epigenetic factors associated with low back pain could be useful in clinical practice. The aim of this study was to review the available literature regarding the epigenetic factors associated with low back pain. This review was carried out in accordance with Preferential Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search was carried out in October 2022. Only peer-reviewed articles were considered for inclusion. Fourteen studies were included and showed promising results in terms of reliable markers. Epigenetic markers for LBP have the potential to significantly modify disease management. Most recent evidence suggests that epigenetics is a more promising field for the identification of factors associated with LBP, offering a rationale for further investigation in this field with the long-term goal of finding epigenetic biomarkers that could constitute biological targets for disease management and treatment. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

19 pages, 1893 KiB

Open AccessReview

Microbiomes, Epigenomics, Immune Response, and Splicing Signatures Interplay: Potential Use of Combination of Regulatory Pathways as Targets for Malignant Mesothelioma

by Botle Precious Setlai, Zilungile Lynette Mkhize-Kwitshana, Ravi Mehrotra, Thanyani Victor Mulaudzi and Zodwa Dlamini

Int. J. Mol. Sci. 2022, 23(16), 8991; https://doi.org/10.3390/ijms23168991 - 12 Aug 2022

Cited by 2 | Viewed by 2279

Abstract

Malignant mesotheliomas (MM) are hard to treat malignancies with poor prognosis and high mortality rates. This cancer is highly misdiagnosed in Sub-Saharan African countries. According to literature, the incidence of MM is likely to increase particularly in low-middle-income countries (LMICs). The burden of [...] Read more.

Malignant mesotheliomas (MM) are hard to treat malignancies with poor prognosis and high mortality rates. This cancer is highly misdiagnosed in Sub-Saharan African countries. According to literature, the incidence of MM is likely to increase particularly in low-middle-income countries (LMICs). The burden of asbestos-induced diseases was estimated to be about 231,000 per annum. Lack of awareness and implementation of regulatory frameworks to control exposure to asbestos fibers contributes to the expected increase. Exposure to asbestos fibers can lead to cancer initiation by several mechanisms. Asbestos-induced epigenetic modifications of gene expression machinery and non-coding RNAs promote cancer initiation and progression. Furthermore, microbiome–epigenetic interactions control the innate and adaptive immunity causing exacerbation of cancer progression and therapeutic resistance. This review discusses epigenetic mechanisms with more focus on miRNAs and their interaction with the microbiome. The potential use of epigenetic alterations and microbiota as specific biomarkers to aid in the early detection and/or development of therapeutic targets is explored. The advancement of combinatorial therapies to prolong overall patient survival or possible eradication of MM especially if it is detected early is discussed. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 3.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Epigenetic Mechanisms and Human Pathology 3.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Related Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI