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Genes May 2024Lysine acetyltransferase 8, also known as KAT8, is an enzyme involved in epigenetic regulation, primarily recognized for its ability to modulate histone acetylation.... (Review)
Review
Lysine acetyltransferase 8, also known as KAT8, is an enzyme involved in epigenetic regulation, primarily recognized for its ability to modulate histone acetylation. This review presents an overview of KAT8, emphasizing its biological functions, which impact many cellular processes and range from chromatin remodeling to genetic and epigenetic regulation. In many model systems, KAT8's acetylation of histone H4 lysine 16 (H4K16) is critical for chromatin structure modification, which influences gene expression, cell proliferation, differentiation, and apoptosis. Furthermore, this review summarizes the observed genetic variability within the gene, underscoring the implications of various single nucleotide polymorphisms (SNPs) that affect its functional efficacy and are linked to diverse phenotypic outcomes, ranging from metabolic traits to neurological disorders. Advanced insights into the structural biology of KAT8 reveal its interaction with multiprotein assemblies, such as the male-specific lethal (MSL) and non-specific lethal (NSL) complexes, which regulate a wide range of transcriptional activities and developmental functions. Additionally, this review focuses on KAT8's roles in cellular homeostasis, stem cell identity, DNA damage repair, and immune response, highlighting its potential as a therapeutic target. The implications of KAT8 in health and disease, as evidenced by recent studies, affirm its importance in cellular physiology and human pathology.
Topics: Humans; Epigenesis, Genetic; Histone Acetyltransferases; Acetylation; Histones; Polymorphism, Single Nucleotide; Animals; Chromatin Assembly and Disassembly
PubMed: 38790268
DOI: 10.3390/genes15050639 -
Genes Apr 2024Cervical cancer is among the highest-ranking types of cancer worldwide, with human papillomavirus (HPV) as the agent driving the malignant process. One aspect of the...
BACKGROUND
Cervical cancer is among the highest-ranking types of cancer worldwide, with human papillomavirus (HPV) as the agent driving the malignant process. One aspect of the infection's evolution is given by epigenetic modifications, mainly DNA methylation and chromatin alteration. These processes are guided by several chromatin remodeling complexes, including NuRD. The purpose of this study was to evaluate the genome-wide binding patterns of the NuRD complex components (MBD2 and MBD3) in the presence of active HPV16 E6 and E7 oncogenes and to determine the potential of identified genes through an experimental model to differentiate between cervical precursor lesions, with the aim of establishing their utility as biomarkers.
METHODS
The experimental model was built using the CaSki cell line and shRNA for E6 and E7 HPV16 silencing, ChIP-seq, qRT-PCR, and Western blot analyses. Selected genes' expression was also assessed in patients.
RESULTS
Several genes have been identified to exhibit altered transcriptional activity due to the influence of HPV16 E6/E7 viral oncogenes acting through the MBD2/MBD3 NuRD complex, linking them to viral infection and cervical oncogenesis.
CONCLUSIONS
The impacted genes primarily play roles in governing gene transcription, mRNA processing, and regulation of translation. Understanding these mechanisms offers valuable insights into the process of HPV-induced oncogenesis.
Topics: Humans; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Uterine Cervical Neoplasms; Papillomavirus E7 Proteins; Oncogene Proteins, Viral; DNA-Binding Proteins; Female; Chromatin Assembly and Disassembly; Repressor Proteins; Cell Line, Tumor; Human papillomavirus 16; Carcinogenesis; Papillomavirus Infections; Gene Expression Regulation, Neoplastic
PubMed: 38790189
DOI: 10.3390/genes15050560 -
Epigenetics & Chromatin May 2024The three-dimensional organization of the genome plays a central role in the regulation of cellular functions, particularly in the human brain. This review explores the... (Review)
Review
The three-dimensional organization of the genome plays a central role in the regulation of cellular functions, particularly in the human brain. This review explores the intricacies of chromatin organization, highlighting the distinct structural patterns observed between neuronal and non-neuronal brain cells. We integrate findings from recent studies to elucidate the characteristics of various levels of chromatin organization, from differential compartmentalization and topologically associating domains (TADs) to chromatin loop formation. By defining the unique chromatin landscapes of neuronal and non-neuronal brain cells, these distinct structures contribute to the regulation of gene expression specific to each cell type. In particular, we discuss potential functional implications of unique neuronal chromatin organization characteristics, such as weaker compartmentalization, neuron-specific TAD boundaries enriched with active histone marks, and an increased number of chromatin loops. Additionally, we explore the role of Polycomb group (PcG) proteins in shaping cell-type-specific chromatin patterns. This review further emphasizes the impact of variations in chromatin architecture between neuronal and non-neuronal cells on brain development and the onset of neurological disorders. It highlights the need for further research to elucidate the details of chromatin organization in the human brain in order to unravel the complexities of brain function and the genetic mechanisms underlying neurological disorders. This research will help bridge a significant gap in our comprehension of the interplay between chromatin structure and cell functions.
Topics: Humans; Neurons; Chromatin; Animals; Brain; Polycomb-Group Proteins; Chromatin Assembly and Disassembly
PubMed: 38783373
DOI: 10.1186/s13072-024-00538-6 -
Nature Communications May 2024Topologically associating domains (TADs), megabase-scale features of chromatin spatial architecture, are organized in a domain-within-domain TAD hierarchy. Within TADs,...
Topologically associating domains (TADs), megabase-scale features of chromatin spatial architecture, are organized in a domain-within-domain TAD hierarchy. Within TADs, the inner and smaller subTADs not only manifest cell-to-cell variability, but also precisely regulate transcription and differentiation. Although over 20 TAD callers are able to detect TAD, their usability in biomedicine is confined by a disagreement of outputs and a limit in understanding TAD hierarchy. We compare 13 computational tools across various conditions and develop a metric to evaluate the similarity of TAD hierarchy. Although outputs of TAD hierarchy at each level vary among callers, data resolutions, sequencing depths, and matrices normalization, they are more consistent when they have a higher similarity of larger TADs. We present comprehensive benchmarking of TAD hierarchy callers and operational guidance to researchers of life science researchers. Moreover, by simulating the mixing of different types of cells, we confirm that TAD hierarchy is generated not simply from stacking Hi-C heatmaps of heterogeneous cells. Finally, we propose an air conditioner model to decipher the role of TAD hierarchy in transcription.
Topics: Benchmarking; Chromatin; Humans; Computational Biology; Software; Chromatin Assembly and Disassembly
PubMed: 38782890
DOI: 10.1038/s41467-024-48593-7 -
Journal of Clinical and Translational... May 2024Hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and liver cancer, and its treatment continues to be difficult. We previously demonstrated that a...
BACKGROUND AND AIMS
Hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and liver cancer, and its treatment continues to be difficult. We previously demonstrated that a dopamine analog inhibited the packaging of pregenomic RNA into capsids. The present study aimed to determine the effect of dopamine on the expressions of hepatitis B virus surface and e antigens (HBsAg and HBeAg, respectively) and to elucidate the underlying mechanism.
METHODS
We used dopamine-treated HBV-infected HepG2.2.15 and NTCP-G2 cells to monitor HBsAg and HBeAg expression levels. We analyzed interferon-stimulated gene 15 (ISG15) expression in dopamine-treated cells. We knocked down ISG15 and then monitored HBsAg and HBeAg expression levels. We analyzed the expression of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway factors in dopamine-treated cells. We used dopamine hydrochloride-treated adeno-associated virus/HBV-infected mouse model to evaluate HBV DNA, HBsAg, and HBeAg expression. HBV virus was collected from HepAD38.7 cell culture medium.
RESULTS
Dopamine inhibited HBsAg and HBeAg expression and upregulated ISG15 expression in HepG2.2.15 and HepG2-NTCP cell lines. ISG15 knockdown increased HBsAg and HBeAg expression in HepG2.2.15 cells. Dopamine-treated cells activated the JAK/STAT pathway, which upregulated ISG15 expression. In the adeno-associated virus-HBV murine infection model, dopamine downregulated HBsAg and HBeAg expression and activated the JAK-STAT/ISG15 axis.
CONCLUSIONS
Dopamine inhibits the expression of HBsAg and HBeAg by activating the JAK/STAT pathway and upregulating ISG15 expression.
PubMed: 38779516
DOI: 10.14218/JCTH.2024.00051 -
FEMS Yeast Research Jan 2024Candida albicans is a human colonizer and also an opportunistic yeast occupying different niches that are mostly hypoxic. While hypoxia is the prevalent condition within...
Candida albicans is a human colonizer and also an opportunistic yeast occupying different niches that are mostly hypoxic. While hypoxia is the prevalent condition within the host, the machinery that integrates oxygen status to tune the fitness of fungal pathogens remains poorly characterized. Here, we uncovered that Snf5, a subunit of the chromatin remodeling complex SWI/SNF, is required to tolerate antifungal stress particularly under hypoxia. RNA-seq profiling of snf5 mutant exposed to amphotericin B and fluconazole under hypoxic conditions uncovered a signature that is reminiscent of copper (Cu) starvation. We found that under hypoxic and Cu-starved environments, Snf5 is critical for preserving Cu homeostasis and the transcriptional modulation of the Cu regulon. Furthermore, snf5 exhibits elevated levels of reactive oxygen species and an increased sensitivity to oxidative stress principally under hypoxia. Supplementing growth medium with Cu or increasing gene dosage of the Cu transporter CTR1 alleviated snf5 growth defect and attenuated reactive oxygen species levels in response to antifungal challenge. Genetic interaction analysis suggests that Snf5 and the bona fide Cu homeostasis regulator Mac1 function in separate pathways. Together, our data underlined a unique role of SWI/SNF complex as a potent regulator of Cu metabolism and antifungal stress under hypoxia.
Topics: Copper; Candida albicans; Antifungal Agents; Oxidative Stress; Gene Expression Regulation, Fungal; Chromatin Assembly and Disassembly; Fungal Proteins; Transcription Factors; Reactive Oxygen Species; Fluconazole; Anaerobiosis; Amphotericin B
PubMed: 38760885
DOI: 10.1093/femsyr/foae018 -
Nature Communications May 2024The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow...
The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.
Topics: Multiple Myeloma; Humans; Chromatin Assembly and Disassembly; Tumor Microenvironment; Cell Line, Tumor; Mesenchymal Stem Cells; Gene Expression Regulation, Neoplastic; Transcription, Genetic; Bone Marrow Cells; Cell Movement; Stromal Cells; Female; Male
PubMed: 38755155
DOI: 10.1038/s41467-024-47793-5 -
Nature Communications May 2024Polymerized β-actin may provide a structural basis for chromatin accessibility and actin transport into the nucleus can guide mesenchymal stem cell (MSC)...
Polymerized β-actin may provide a structural basis for chromatin accessibility and actin transport into the nucleus can guide mesenchymal stem cell (MSC) differentiation. Using MSC, we show that using CK666 to inhibit Arp2/3 directed secondary actin branching results in decreased nuclear actin structure, and significantly alters chromatin access measured with ATACseq at 24 h. The ATAC-seq results due to CK666 are distinct from those caused by cytochalasin D (CytoD), which enhances nuclear actin structure. In addition, nuclear visualization shows Arp2/3 inhibition decreases pericentric H3K9me3 marks. CytoD, alternatively, induces redistribution of H3K27me3 marks centrally. Such alterations in chromatin landscape are consistent with differential gene expression associated with distinctive differentiation patterns. Further, knockdown of the non-enzymatic monomeric actin binding protein, Arp4, leads to extensive chromatin unpacking, but only a modest increase in transcription, indicating an active role for actin-Arp4 in transcription. These data indicate that dynamic actin remodeling can regulate chromatin interactions.
Topics: Actins; Chromatin; Cell Nucleus; Actin-Related Protein 2-3 Complex; Mesenchymal Stem Cells; Animals; Cell Differentiation; Cytochalasin D; Histones; Humans; Microfilament Proteins; Mice; Chromatin Assembly and Disassembly
PubMed: 38750021
DOI: 10.1038/s41467-024-48580-y -
Biomedicine & Pharmacotherapy =... Jun 2024Schizophrenia, influenced by genetic and environmental factors, may involve epigenetic alterations, notably histone modifications, in its pathogenesis. This review... (Review)
Review
Schizophrenia, influenced by genetic and environmental factors, may involve epigenetic alterations, notably histone modifications, in its pathogenesis. This review summarizes various histone modifications including acetylation, methylation, phosphorylation, ubiquitination, serotonylation, lactylation, palmitoylation, and dopaminylation, and their implications in schizophrenia. Current research predominantly focuses on histone acetylation and methylation, though other modifications also play significant roles. These modifications are crucial in regulating transcription through chromatin remodeling, which is vital for understanding schizophrenia's development. For instance, histone acetylation enhances transcriptional efficiency by loosening chromatin, while increased histone methyltransferase activity on H3K9 and altered histone phosphorylation, which reduces DNA affinity and destabilizes chromatin structure, are significant markers of schizophrenia.
Topics: Schizophrenia; Humans; Histones; Animals; Epigenesis, Genetic; Protein Processing, Post-Translational; Acetylation; Methylation; Phosphorylation; Chromatin Assembly and Disassembly
PubMed: 38744217
DOI: 10.1016/j.biopha.2024.116747 -
Genome Biology May 2024Pluripotent states of embryonic stem cells (ESCs) with distinct transcriptional profiles affect ESC differentiative capacity and therapeutic potential. Although...
BACKGROUND
Pluripotent states of embryonic stem cells (ESCs) with distinct transcriptional profiles affect ESC differentiative capacity and therapeutic potential. Although single-cell RNA sequencing has revealed additional subpopulations and specific features of naive and primed human pluripotent stem cells (hPSCs), the underlying mechanisms that regulate their specific transcription and that control their pluripotent states remain elusive.
RESULTS
By single-cell analysis of high-resolution, three-dimensional (3D) genomic structure, we herein demonstrate that remodeling of genomic structure is highly associated with the pluripotent states of human ESCs (hESCs). The naive pluripotent state is featured with specialized 3D genomic structures and clear chromatin compartmentalization that is distinct from the primed state. The naive pluripotent state is achieved by remodeling the active euchromatin compartment and reducing chromatin interactions at the nuclear center. This unique genomic organization is linked to enhanced chromatin accessibility on enhancers and elevated expression levels of naive pluripotent genes localized to this region. In contradistinction, the primed state exhibits intermingled genomic organization. Moreover, active euchromatin and primed pluripotent genes are distributed at the nuclear periphery, while repressive heterochromatin is densely concentrated at the nuclear center, reducing chromatin accessibility and the transcription of naive genes.
CONCLUSIONS
Our data provide insights into the chromatin structure of ESCs in their naive and primed states, and we identify specific patterns of modifications in transcription and chromatin structure that might explain the genes that are differentially expressed between naive and primed hESCs. Thus, the inversion or relocation of heterochromatin to euchromatin via compartmentalization is related to the regulation of chromatin accessibility, thereby defining pluripotent states and cellular identity.
Topics: Humans; Single-Cell Analysis; Pluripotent Stem Cells; Genome, Human; Euchromatin; Chromatin; Human Embryonic Stem Cells; Heterochromatin; Embryonic Stem Cells; Chromatin Assembly and Disassembly
PubMed: 38741214
DOI: 10.1186/s13059-024-03268-w