Histone Modifications in Health and Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 12101

Special Issue Editors


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Guest Editor
Center for Molecular and Translational Medicine, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
Interests: epigenetics; histone modifications; vascular biology; gastroenterological disorders; metabolic diseases
Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA
Interests: SMYD proteins; structure and function relationships; data science
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Guest Editor
Cancer Animal Models Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
Interests: epigenetics; cancer biology; gastroenterological disorders; animal disease models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Histones undergo a variety of post-translational modifications (PTMs), the covalent modifications on certain residues of histone proteins, including acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, and ADP-ribosylation, among others. These PTMs can impact gene expression by altering chromatin structure and function, regulating transcription and other nuclear processes, recruiting reader/binding proteins, etc.

Histone PTMs are dynamically regulated by specific modifying enzymes whose activities require metabolites that either serve as co-substrates or act as activators/inhibitors. Aberrant histone modifications are linked to the pathogenesis and progression of a multitude of human diseases such as cancers, cardiovascular diseases, autoimmune diseases, as well as other inflammatory and metabolic disorders. Thus, elucidating the molecular mechanisms underlying histone modifications in health and disease conditions is critical to understanding disease pathogenesis and the development of novel therapeutics.

This Special Issue on “Histone Modifications in Health and Diseases” aims to provide new insights into the mechanisms and dysregulation of various histone modifications in human health and diseases. Authors are invited to submit original research and review articles related to these subjects. The topics of interest include (but are not limited to) novel aspects and mechanisms of histone modifications, role of histone posttranslational modifications in disease development, crosstalk between different histone modifications and its role in health and disease, application of activators/inhibitors of histone-modifying enzymes in disease control, etc.

Dr. Chunying Li
Dr. Zhe Yang
Dr. Yuning Hou
Guest Editors

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Keywords

  • histone modifications
  • lysine methylation
  • lysine acetylation
  • histone phosphorylation
  • histone ubiquitylation
  • histone sumoylation
  • human diseases

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Published Papers (4 papers)

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Research

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25 pages, 3866 KiB  
Article
Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells
by Mevan Jacksi, Eva Schad and Agnes Tantos
Biomolecules 2024, 14(4), 445; https://doi.org/10.3390/biom14040445 - 5 Apr 2024
Cited by 1 | Viewed by 1745
Abstract
Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). [...] Read more.
Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial–mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without the EZH2 activity inhibitor 3-deazanoplanocine (DZNep). Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell proliferation became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects in colorectal carcinoma cells. Full article
(This article belongs to the Special Issue Histone Modifications in Health and Diseases)
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17 pages, 4731 KiB  
Article
LEO1 Is Required for Efficient Entry into Quiescence, Control of H3K9 Methylation and Gene Expression in Human Fibroblasts
by Marc Laurent, Lina Cordeddu, Yasaman Zahedi and Karl Ekwall
Biomolecules 2023, 13(11), 1662; https://doi.org/10.3390/biom13111662 - 17 Nov 2023
Viewed by 1675
Abstract
(1) Background: The LEO1 (Left open reading frame 1) protein is a conserved subunit of the PAF1C complex (RNA polymerase II-associated factor 1 complex). PAF1C has well-established mechanistic functions in elongation of transcription and RNA processing. We previously showed, in fission yeast, that [...] Read more.
(1) Background: The LEO1 (Left open reading frame 1) protein is a conserved subunit of the PAF1C complex (RNA polymerase II-associated factor 1 complex). PAF1C has well-established mechanistic functions in elongation of transcription and RNA processing. We previously showed, in fission yeast, that LEO1 controls histone H3K9 methylation levels by affecting the turnover of histone H3 in chromatin, and that it is essential for the proper regulation of gene expression during cellular quiescence. Human fibroblasts enter a reversible quiescence state upon serum deprivation in the growth media. Here we investigate the function of LEO1 in human fibroblasts. (2) Methods: We knocked out the LEO1 gene using CRISPR/Cas9 methodology in human fibroblasts and verified that the LEO1 protein was undetectable by Western blot. We characterized the phenotype of the ΔLEO1 knockout cells with FACS analysis and cell growth assays. We used RNA-sequencing using spike-in controls to measure gene expression and spike-in controlled ChIP-sequencing experiments to measure the histone modification H3K9me2 genome-wide. (3) Results: Gene expression levels are altered in quiescent cells, however factors controlling chromatin and gene expression changes in quiescent human cells are largely unknown. The ΔLEO1 knockout fibroblasts are viable but have reduced metabolic activity compared to wild-type cells. ΔLEO1 cells showed a slower entry into quiescence and a different morphology compared to wild-type cells. Gene expression was generally reduced in quiescent wild-type cells. The downregulated genes included genes involved in cell proliferation. A small number of genes were upregulated in quiescent wild-type cells including several genes involved in ERK1/ERK2 and Wnt signaling. In quiescent ΔLEO1 cells, many genes were mis-regulated compared to wild-type cells. This included genes involved in Calcium ion transport and cell morphogenesis. Finally, spike-in controlled ChIP-sequencing experiments demonstrated that the histone modification H3K9me2 levels are globally increased in quiescent ΔLEO1 cells. (4) Conclusions: Thus, LEO1 is important for proper entry into cellular quiescence, control of H3K9me2 levels, and gene expression in human fibroblasts. Full article
(This article belongs to the Special Issue Histone Modifications in Health and Diseases)
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Review

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11 pages, 1473 KiB  
Review
LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond
by Hyun-Min Kim and Zifei Liu
Biomolecules 2024, 14(5), 553; https://doi.org/10.3390/biom14050553 - 3 May 2024
Viewed by 1627
Abstract
Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with [...] Read more.
Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2’s implications. While both share structural similarities, LSD2 possesses unique features as well. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation, cancer cell reprogramming, E3 ubiquitin ligase activity and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes. Full article
(This article belongs to the Special Issue Histone Modifications in Health and Diseases)
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20 pages, 1671 KiB  
Review
New Targets and Strategies for Rheumatoid Arthritis: From Signal Transduction to Epigenetic Aspect
by Menglin Zhu, Qian Ding, Zhongxiao Lin, Rong Fu, Fuyuan Zhang, Zhaoyi Li, Mei Zhang and Yizhun Zhu
Biomolecules 2023, 13(5), 766; https://doi.org/10.3390/biom13050766 - 28 Apr 2023
Cited by 12 | Viewed by 6024
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint damage and even permanent disability, seriously affecting patients’ quality of life. At present, the complete cure for RA is not achievable, only to relieve the symptoms to reduce the pain [...] Read more.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint damage and even permanent disability, seriously affecting patients’ quality of life. At present, the complete cure for RA is not achievable, only to relieve the symptoms to reduce the pain of patients. Factors such as environment, genes, and sex can induce RA. Presently, non-steroidal anti-inflammatory drugs, DRMADs, and glucocorticoids are commonly used in treating RA. In recent years, some biological agents have also been applied in clinical practice, but most have side effects. Therefore, finding new mechanisms and targets for treating RA is necessary. This review summarizes some potential targets discovered from the perspective of epigenetics and RA mechanisms. Full article
(This article belongs to the Special Issue Histone Modifications in Health and Diseases)
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