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Biochemical Society Transactions Jun 2024Nucleosomes constitute the fundamental building blocks of chromatin. They are comprised of DNA wrapped around a histone octamer formed of two copies each of the four... (Review)
Review
Nucleosomes constitute the fundamental building blocks of chromatin. They are comprised of DNA wrapped around a histone octamer formed of two copies each of the four core histones H2A, H2B, H3, and H4. Nucleosomal histones undergo a plethora of posttranslational modifications that regulate gene expression and other chromatin-templated processes by altering chromatin structure or by recruiting effector proteins. Given their symmetric arrangement, the sister histones within a nucleosome have commonly been considered to be equivalent and to carry the same modifications. However, it is now clear that nucleosomes can exhibit asymmetry, combining differentially modified sister histones or different variants of the same histone within a single nucleosome. Enabled by the development of novel tools that allow generating asymmetrically modified nucleosomes, recent biochemical and cell-based studies have begun to shed light on the origins and functional consequences of nucleosomal asymmetry. These studies indicate that nucleosomal asymmetry represents a novel regulatory mechanism in the establishment and functional readout of chromatin states. Asymmetry expands the combinatorial space available for setting up complex sets of histone marks at individual nucleosomes, regulating multivalent interactions with histone modifiers and readers. The resulting functional consequences of asymmetry regulate transcription, poising of developmental gene expression by bivalent chromatin, and the mechanisms by which oncohistones deregulate chromatin states in cancer. Here, we review recent progress and current challenges in uncovering the mechanisms and biological functions of nucleosomal asymmetry.
Topics: Nucleosomes; Histones; Humans; Animals; Protein Processing, Post-Translational; Chromatin; Chromatin Assembly and Disassembly
PubMed: 38778762
DOI: 10.1042/BST20230877 -
Nature Structural & Molecular Biology May 2024Hexasomes are non-canonical nucleosomes that package DNA with six instead of eight histones. First discovered 40 years ago as a consequence of transcription, two... (Review)
Review
Hexasomes are non-canonical nucleosomes that package DNA with six instead of eight histones. First discovered 40 years ago as a consequence of transcription, two near-atomic-resolution cryo-EM structures of the hexasome in complex with the chromatin remodeler INO80 have now started to unravel its mechanistic impact on the regulatory landscape of chromatin. Loss of one histone H2A-H2B dimer converts inactive nucleosomes into distinct and favorable substrates for ATP-dependent chromatin remodeling.
Topics: Chromatin Assembly and Disassembly; Nucleosomes; Histones; Cryoelectron Microscopy; Models, Molecular; Humans; Saccharomyces cerevisiae Proteins; DNA
PubMed: 38769465
DOI: 10.1038/s41594-024-01278-7 -
Nature Genetics Jun 2024
Topics: Chromatin; Transcription, Genetic; Humans; Animals; Chromatin Assembly and Disassembly; Histones; Gene Expression Regulation; Genome
PubMed: 38769458
DOI: 10.1038/s41588-024-01705-x -
The Journals of Gerontology. Series A,... Jul 2024Epigenetic changes have been established to be a hallmark of aging, which implies that aging science requires collaborating with the field of chromatin biology. DNA... (Review)
Review
Epigenetic changes have been established to be a hallmark of aging, which implies that aging science requires collaborating with the field of chromatin biology. DNA methylation patterns, changes in relative abundance of histone post-translational modifications, and chromatin remodeling are the central players in modifying chromatin structure. Aging is commonly associated with an overall increase in chromatin instability, loss of homeostasis, and decondensation. However, numerous publications have highlighted that the link between aging and chromatin changes is not nearly as linear as previously expected. This complex interplay of these epigenetic elements during the lifetime of an organism likely contributes to cellular senescence, genomic instability, and disease susceptibility. Yet, the causal links between these phenomena still need to be fully unraveled. In this perspective article, we discuss potential future directions of aging chromatin biology.
Topics: Humans; Aging; Chromatin; Neoplasms; Epigenesis, Genetic; Cellular Senescence; Genomic Instability; Chromatin Assembly and Disassembly; DNA Methylation; Histones; Animals; Protein Processing, Post-Translational
PubMed: 38761362
DOI: 10.1093/gerona/glae133 -
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 -
Cell Reports May 2024CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or...
CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.
Topics: Humans; Homeodomain Proteins; Hematopoietic Stem Cells; Chromatin; Repressor Proteins; Transcription Factors; Animals; Mice; Nuclear Proteins; Cell Lineage; Chromatin Assembly and Disassembly; Cell Differentiation; DNA-Binding Proteins; Enhancer Elements, Genetic
PubMed: 38735044
DOI: 10.1016/j.celrep.2024.114227