Histone H4K20 Trimethylation Is Decreased in Murine Models of Heart Disease

Hickenlooper, Samuel; Davis, Kathryn; Szulik, Marta W.; Sheikh, Hanin; Miller, Matt; Valdez, Steven; Bia, Ryan; Franklin, Sarah

doi:10.1021/acsomega.2c00984

Cited by 5 publications

(3 citation statements)

References 57 publications

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“…Another gene that is involved in the regulation of chromatin is Kmt5a (FC=-1.90) that regulates lysine-20 methylation in histone H4. Recent results showed a direct link between the lysine methylation at this site and the heart failure in mice and humans (57).…”

Section: Discussionmentioning

confidence: 99%

Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA)

Du,

Sudlow,

Biswas

et al. 2024

Preprint

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The successful treatment of side effects of chemotherapy faces two major limitations: the need to avoid interfering with pathways essential for the cancer-destroying effects of the chemotherapy drug, and the need to avoid helping tumor progression through cancer promoting cellular pathways. To address these questions and identify new pathways and targets that satisfy these limitations, we have developed the bioinformatics tool Inter Variability Cross-Correlation Analysis (IVCCA). This tool calculates the cross-correlation of differentially expressed genes, analyzes their clusters, and compares them across a vast number of known pathways to identify the most relevant target(s). To demonstrate the utility of IVCCA, we applied this platform to RNA-seq data obtained from the hearts of the animal models with oxaliplatin-induced CTX. RNA-seq of the heart tissue from oxaliplatin treated mice identified 1744 differentially expressed genes with False Discovery Rate (FDR) less than 0.05 and fold change above 1.5 across nine samples. We compared the results against traditional gene enrichment analysis methods, revealing that IVCCA identified additional pathways potentially involved in CTX beyond those detected by conventional approaches. The newly identified pathways such as energy metabolism and several others represent promising target for therapeutic intervention against CTX, while preserving the efficacy of the chemotherapy treatment and avoiding tumor proliferation. Targeting these pathways is expected to mitigate the damaging effects of chemotherapy on cardiac tissues and improve patient outcomes by reducing the incidence of heart failure and other cardiovascular complications, ultimately enabling patients to complete their full course of chemotherapy with improved quality of life and survival rates.

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Section: Discussionmentioning

confidence: 99%

Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA)

Du,

Sudlow,

Biswas

et al. 2024

Preprint

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“…HMTs, which assist in histone methylation and modify histone arginine or lysine residues, play a role in maintaining chromatin status and are associated with DNA repair, mitosis, and cell-cycle regulation [ 137 , 138 ]. The histone lysine methyltransferase family predominantly regulates histone H3 N-terminal tails and H4 N-terminal lysine residues, each of which undergoes methyl transfer but forms a trimethylated derivative at most [ 139 ].…”

Section: Types Of Chromatin Modifiersmentioning

confidence: 99%

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

Nie,

Song,

Huang

et al. 2024

Mol Biomed

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The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by regulating chromatin accessibility and the ability of transcription factors to acquire DNA. This is achieved by recruiting associated proteins and RNA polymerases. They modify the physical contact between cis-regulatory factor elements, transcription factors, and chromatin DNA to influence transcriptional regulatory processes. Then, abnormal chromatin perturbations can impair the homeostasis of organs, tissues, and cells, leading to diseases. The review offers a comprehensive elucidation on the function and regulatory mechanism of chromatin modifiers, thereby highlighting their indispensability in the development of diseases. Furthermore, this underscores the potential of chromatin modifiers as biomarkers, which may enable early disease diagnosis. With the aid of this paper, a deeper understanding of the role of chromatin modifiers in the pathogenesis of diseases can be gained, which could help in devising effective diagnostic and therapeutic interventions.

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“…Similarly, another modification, H4K20 trimethylation, is reduced during prolonged ischemia injury and cardiac dysfunction in animal models, and the enzymes responsible for adding and removing methyl groups are regulated distinctly in heart failure. Further studies will be required to clarify the cardiac role of these enzymes in heart failure [41].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of heart failure

Deogharia,

Gurha

2024

Current Opinion in Cardiology

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Purpose of review The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure. Recent findings We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed. New findings from the studies of histone lysine demethylases demonstrate their significance in regulating fetal gene expression, as well as their aberrant expression in adult hearts during HF. Similarly, the relevance of histone deacetylases inhibition in heart failure and the role of HDAC6 in cardio-protection are discussed. Finally, the role of LMNA (lamin A/C), a nuclear membrane protein that interacts with chromatin to form hundreds of large chromatin domains known as lamin-associated domains (LADs), and 3D genome structure in epigenetic regulation of gene expression and heart failure is discussed. Summary Epigenetic modifications provide a mechanism for responding to stress and environmental variation, enabling reactions to both external and internal stimuli, and their dysregulation can be pathological as in heart failure. To gain a thorough understanding of the pathological mechanisms and to aid in the development of targeted treatments for heart failure, future research on studying the combined effects of numerous epigenetic changes and the structure of chromatin is warranted.

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Histone H4K20 Trimethylation Is Decreased in Murine Models of Heart Disease

Cited by 5 publications

References 57 publications

Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA)

Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA)

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

Epigenetic regulation of heart failure

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