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Proceedings of the National Academy of... May 2023Prostaglandin E2 (PGE) and 16,16-dimethyl-PGE (dmPGE) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem...
Prostaglandin E2 (PGE) and 16,16-dimethyl-PGE (dmPGE) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler , 3074-3081(2013); W. Goessling , 445-458 (2011); W. Goessling , 1136-1147 (2009)]. Here, we report that PGE-induced changes in chromatin at enhancer regions through histone-variant H2A.Z permit acute inflammatory gene induction to promote HSPC fate. We found that dmPGE-inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE stimulation is concomitant with deposition of histone acetyltransferases p300 and Tip60 on chromatin. Subsequent H2A.Z acetylation improves chromatin accessibility at stimuli-responsive enhancers. Our findings support a model where histone-variant nucleosomes retained within inducible enhancers facilitate TF binding. Histone-variant acetylation by TF-associated nucleosome remodelers creates the accessible nucleosome landscape required for immediate enhancer activation and gene induction. Our work provides a mechanism through which inflammatory mediators, such as dmPGE, lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation.
Topics: Nucleosomes; Histones; Chromatin; Dinoprostone; Regulatory Sequences, Nucleic Acid; Chromatin Assembly and Disassembly
PubMed: 37126722
DOI: 10.1073/pnas.2220613120 -
ACS Chemical Biology Mar 2022The formation of chromatin not only compacts the eukaryotic genome into the nucleus but also provides a mechanism for the regulation of all DNA templated processes.... (Review)
Review
The formation of chromatin not only compacts the eukaryotic genome into the nucleus but also provides a mechanism for the regulation of all DNA templated processes. Spatial and temporal modulation of the chromatin structure is critical in such regulation and involves fine-tuned functioning of the basic subunit of chromatin, the nucleosome. It has become apparent that the nucleosome is an inherently dynamic system, but characterization of these dynamics at the atomic level has remained challenging. NMR spectroscopy is a powerful tool for investigating the conformational ensemble and dynamics of proteins and protein complexes, and recent advances have made the study of large systems possible. Here, we review recent studies which utilize NMR spectroscopy to uncover the atomic level conformation and dynamics of the nucleosome and provide a better understanding of the importance of these dynamics in key regulatory events.
Topics: Chromatin; Chromatin Assembly and Disassembly; Magnetic Resonance Spectroscopy; Molecular Conformation; Nucleosomes
PubMed: 35196453
DOI: 10.1021/acschembio.1c00954 -
International Journal of Molecular... Feb 2024Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions,... (Review)
Review
Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions, causes organ failure, and can, in extreme cases, compromise the functionality of organs to the point of causing death. In recent years, considerable efforts have been made to understand the molecular mechanisms underlying fibrotic evolution and to identify possible therapeutic strategies. Great interest has been aroused by the discovery of a molecular association between epithelial to mesenchymal plasticity (EMP), in particular epithelial to mesenchymal transition (EMT), and fibrogenesis, which has led to the identification of complex molecular mechanisms closely interconnected with each other, which could explain EMT-dependent fibrosis. However, the result remains unsatisfactory from a therapeutic point of view. In recent years, advances in epigenetics, based on chromatin remodeling through various histone modifications or through the intervention of non-coding RNAs (ncRNAs), have provided more information on the fibrotic process, and this could represent a promising path forward for the identification of innovative therapeutic strategies for organ fibrosis. In this review, we summarize current research on epigenetic mechanisms involved in organ fibrosis, with a focus on epigenetic regulation of EMP/EMT-dependent fibrosis.
Topics: Humans; Epigenesis, Genetic; DNA Methylation; Epithelial-Mesenchymal Transition; Fibrosis; Chromatin Assembly and Disassembly
PubMed: 38474021
DOI: 10.3390/ijms25052775 -
Genes Jun 2021Hematopoiesis is a convenient model to study how chromatin dynamics plays a decisive role in regulation of cell fate. During erythropoiesis a population of stem and... (Review)
Review
Hematopoiesis is a convenient model to study how chromatin dynamics plays a decisive role in regulation of cell fate. During erythropoiesis a population of stem and progenitor cells becomes increasingly lineage restricted, giving rise to terminally differentiated progeny. The concerted action of transcription factors and epigenetic modifiers leads to a silencing of the multipotent transcriptome and activation of the transcriptional program that controls terminal differentiation. This article reviews some aspects of the biology of red blood cells production with the focus on the extensive chromatin reorganization during differentiation.
Topics: Animals; Cell Differentiation; Cell Lineage; Chromatin Assembly and Disassembly; Erythroid Precursor Cells; Erythropoiesis; Gene Expression Regulation; Genome; Humans; Transcription Factors
PubMed: 34208866
DOI: 10.3390/genes12071012 -
International Journal of Molecular... Jan 2020HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of... (Review)
Review
HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology.
Topics: Animals; Cell Cycle; Chromatin Assembly and Disassembly; Embryonic Development; Evolution, Molecular; Gene Expression Regulation, Developmental; HMGA Proteins; Humans
PubMed: 31963852
DOI: 10.3390/ijms21020654 -
Nature Communications Dec 2023ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF...
ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.
Topics: Transcription Factors; Chromatin; Chromatin Assembly and Disassembly; Cell Differentiation; Hematopoietic Stem Cells
PubMed: 38102116
DOI: 10.1038/s41467-023-44081-6 -
F1000Research 2020ATP-dependent chromatin remodelling enzymes are molecular machines that act to reconfigure the structure of nucleosomes. Until recently, little was known about the... (Review)
Review
ATP-dependent chromatin remodelling enzymes are molecular machines that act to reconfigure the structure of nucleosomes. Until recently, little was known about the structure of these enzymes. Recent progress has revealed that their interaction with chromatin is dominated by ATPase domains that contact DNA at favoured locations on the nucleosome surface. Contacts with histones are limited but play important roles in modulating activity. The ATPase domains do not act in isolation but are flanked by diverse accessory domains and subunits. New structures indicate how these subunits are arranged in multi-subunit complexes providing a framework from which to understand how a common motor is applied to distinct functions.
Topics: Chromatin; Chromatin Assembly and Disassembly; DNA; Histones; Nucleosomes
PubMed: 32864100
DOI: 10.12688/f1000research.21933.1 -
The EMBO Journal Dec 2022Mammalian SWI/SNF/BAF chromatin remodeling complexes influence cell lineage determination. While the contribution of these complexes to neural progenitor cell (NPC)...
Mammalian SWI/SNF/BAF chromatin remodeling complexes influence cell lineage determination. While the contribution of these complexes to neural progenitor cell (NPC) proliferation and differentiation has been reported, little is known about the transcriptional profiles that determine neurogenesis or gliogenesis. Here, we report that BCL7A is a modulator of the SWI/SNF/BAF complex that stimulates the genome-wide occupancy of the ATPase subunit BRG1. We demonstrate that BCL7A is dispensable for SWI/SNF/BAF complex integrity, whereas it is essential to regulate Notch/Wnt pathway signaling and mitochondrial bioenergetics in differentiating NPCs. Pharmacological stimulation of Wnt signaling restores mitochondrial respiration and attenuates the defective neurogenic patterns observed in NPCs lacking BCL7A. Consistently, treatment with an enhancer of mitochondrial biogenesis, pioglitazone, partially restores mitochondrial respiration and stimulates neuronal differentiation of BCL7A-deficient NPCs. Using conditional BCL7A knockout mice, we reveal that BCL7A expression in NPCs and postmitotic neurons is required for neuronal plasticity and supports behavioral and cognitive performance. Together, our findings define the specific contribution of BCL7A-containing SWI/SNF/BAF complexes to mitochondria-driven NPC commitment, thereby providing a better understanding of the cell-intrinsic transcriptional processes that connect metabolism, neuronal morphogenesis, and cognitive flexibility.
Topics: Animals; Mice; Adenosine Triphosphatases; Chromatin Assembly and Disassembly; Energy Metabolism; Mitochondria; Transcription Factors; Microfilament Proteins; Neural Stem Cells; Cell Differentiation
PubMed: 36305367
DOI: 10.15252/embj.2022110595 -
Current Opinion in Structural Biology Dec 2021The initiation signals are raised around the promoter by one of the general transcription factors, triggering a sequence of events that lead to mRNA transcript formation... (Review)
Review
The initiation signals are raised around the promoter by one of the general transcription factors, triggering a sequence of events that lead to mRNA transcript formation from target genes. Both specific noncoding DNA regions and transacting, macromolecular assemblies are intricately involved and indispensable. The transition between the subsequent transcriptional stages is accompanied by stage-specific signals and structural changes in the macromolecular assemblies and facilitated by the recruitment/removal of other chromatin and transcription-associated elements. Here, we discuss the choreography of transacting factors around promoter in the establishment and effectuation of the initial phases of transcription such as NDR formation, +1 nucleosome positioning, promoter DNA opening, and RNAPII promoter escape from a structural viewpoint.
Topics: Chromatin; Chromatin Assembly and Disassembly; Nucleosomes; Promoter Regions, Genetic; Trans-Activators; Transcription, Genetic
PubMed: 34111671
DOI: 10.1016/j.sbi.2021.04.008 -
Biochemistry Aug 2021We review exciting recent advances in protein degradation, with a focus on chromatin structure. In our analysis of the literature, we highlight studies of kinetic... (Review)
Review
We review exciting recent advances in protein degradation, with a focus on chromatin structure. In our analysis of the literature, we highlight studies of kinetic control of protein stability for cohesin, condensin, ATP-dependent chromatin remodeling, and pioneer transcription factors. With new connections emerging between chromatin remodeling and genome structure, we anticipate exciting developments at the intersection of these topics to be revealed in the coming years. Moreover, we pay special attention to the 20-year anniversary of PROTACs, with an overview of E3 ligase/target pairings and central questions that might lead to the next generation of PROTACs with an expanded scope and generality. While steady-state experimental measurements with constitutive genome editing are impactful, we highlight complementary approaches for rapid kinetic protein degradation to uncover early targeting functions and to understand the central determinants of genome structure-function relationships.
Topics: Chromatin; Chromatin Assembly and Disassembly; Genome; Proteolysis; Structure-Activity Relationship; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 34292716
DOI: 10.1021/acs.biochem.1c00306