Epigenetic marks uniquely tune the material properties of HP1α condensates

Biophysical Journal, Год журнала: 2024, Номер 123(11), С. 1508 - 1518

Опубликована: Апрель 24, 2024

Biomolecular condensates have emerged as a powerful new paradigm in cell biology with broad implications to human health and disease, particularly the nucleus where phase separation is thought underly elements of chromatin organization regulation. Specifically, it has been recently reported that heterochromatin protein 1alpha (HP1α) DNA contributes formation condensed states. HP1α localization heterochromatic regions mediated by its binding specific repressive marks on tail histone H3, such trimethylated lysine 9 H3 (H3K9me3). However, whether epigenetic play an active role modulating material properties dictating emergent functions remains be understood. Here, we leverage reductionist system, composed modified unmodified peptides, HP1α, DNA, examine contribution behavior HP1α. We show presence peptides bearing H3K9me3 compatible condensates, whereas containing residues or transcriptional activation mark H3K4me3 are incompatible separation. Using fluorescence microscopy rheological approaches, further demonstrate modulate dynamics viscoelastic network concentration-dependent manner. Additionally, cells exposed uniaxial strain, find there decreased ratio nuclear These data suggest HP1α-DNA materials, whose may provide explanation for dynamic response mechanostimulation.

Язык: Английский

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Differential transcriptional profiles of vagal sensory neurons in female and male mice

Frontiers in Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Май 14, 2024

Introduction Differences in metabolic homeostasis, diabetes, and obesity between males females are evident rodents humans. Vagal sensory neurons the vagus nerve ganglia innervate a variety of visceral organs use specialized endings to sense interoceptive signals. This organ-brain axis plays role relaying signals higher brain centers, as well regulating vago-vagal reflex. I hypothesized that molecularly distinct populations vagal would play causing differences homeostasis sexes. Methods SnRNA-Seq was conducted on dissociated cells from using 10X Genomics Chromium platform. Results Single-nucleus RNA sequencing analysis female male mice revealed transcriptional profiles ganglia. These linked expression sex-specific genes such Xist , Tsix Ddx3y . Among 13 neuronal clusters, one-fourth were located -enriched VN1 VN8 which displayed enrichment Trpv1 Piezo2 Htr3a Vip genes. In contrast, 70% found clusters VN4, 6, 7, 10, 11, 13, showed enriched Fgfr1 Lpar1 Cpe Esr1 Nrg1 Egfr Oprm1 Two satellite identified, one contained oligodendrocyte precursor mice. A small population expressed Ucp1 Plin1 indicating they epineural adipocytes. Discussion Understanding physiological implications transcriptomic energy balance help develop treatments for dysregulation.

Язык: Английский

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Histone H4 acetylation differentially modulates proliferation in adult oligodendrocyte progenitors

The Journal of Cell Biology, Год журнала: 2024, Номер 223(11)

Опубликована: Авг. 12, 2024

Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis ChIP sequencing of PDGFRα+ OPCs sorted from adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac mark as enriched in aOPCs. We detect increased occupancy at chromatin locations corresponding to genes related progenitor state (e.g., Hes5, Gpr17), metabolic processes Txnip, Ptdgs), myelin components Cnp, Mog). aOPCs showed higher levels transcripts lipid metabolism myelin, lower cell cycle proliferation compared with nOPCs. In addition, pharmacological inhibition acetylation decreased expression target their proliferation. Overall, this study identifies H4K8 a regulator proliferative capacity

Язык: Английский

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The epigenetic landscape of oligodendrocyte progenitors changes with time

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 6, 2024

ABSTRACT SUMMARY Dansu et al. identify distinct histone H4 modifications as potential mechanism underlying the functional differences between adult and neonatal progenitors. While H4K8ac favors expression of differentiation genes, their is halted by H4K20me3. Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes, like (nOPCs), but they also display unique features. Here, using RNA-sequencing, unbiased proteomics analysis ChIP-sequencing, we define transcripts marks properties aOPCs. We describe lower proliferative capacity higher levels specific genes in aOPCs compared to nOPCs, well greater marks. report increased occupancy mark at chromatin locations corresponding oligodendrocyte-specific transcription factors lipid metabolism genes. Pharmacological inhibition deposition reduces these aOPCs, rendering transcriptome more similar nOPCs. The repressive H4K20me3 nOPCs pharmacological its results related mature state. Overall, this study identifies two which are important for transcriptional identity

Язык: Английский

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Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 11, 2024

Abstract Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of central nervous system (CNS). Through transcriptomics imaging analyses, we have identified Obp44a as one most abundantly produced proteins from Drosophila CNS glia. Protein structure homology modeling Nuclear Magnetic Resonance (NMR) experiments reveal a fatty acid binding protein (FABP) with high affinity towards long-chain acids both native oxidized forms. Further analyses demonstrate that effectively infiltrates neuropil, traffics between neuron glia, is secreted into hemolymph, acting lipid chaperone scavenger to regulate redox homeostasis developing brain. In agreement this essential role, deficiency leads anatomical behavioral deficits adult animals elevated levels. Collectively, our findings unveil crucial involvement noncanonical shuttle within outside brain, needed maintain healthy brain environment. These could inspire design novel approaches restore dysregulated diseases.

Язык: Английский

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Enhancers on the edge — how the nuclear envelope controls gene regulatory elements

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 87, С. 102234 - 102234

Опубликована: Июль 22, 2024

Precise temporal and sequential control of gene expression during development in response to environmental stimuli requires tight regulation the physical contact between regulatory elements promoters. Current models describing how genome folds 3D space establish these interactions often ignore role most stable structural nuclear feature — envelope. While contributions folding within/between topologically associated domains (TADs) have been extensively described, mechanical from envelope can impact enhancer–promoter both directly indirectly through influencing intra/inter-TAD interactions. Importantly, clearly link this mechanism and, when defective, human disease. Here, we discuss evidence for tissue-specific pairings, potential mechanisms regulation, exciting recent findings that other such as microRNAs long noncoding RNAs are under possible involvement condensates, disruption lead

Язык: Английский

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Modified histone peptides uniquely tune the material properties of HP1α condensates

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 9, 2024

Abstract Biomolecular condensates have emerged as a powerful new paradigm in cell biology with broad implications to human health and disease, particularly the nucleus where phase separation is thought underly elements of chromatin organization regulation. Specifically, it has been recently reported that heterochromatin protein 1alpha (HP1α) DNA contributes formation condensed states. HP1α localization heterochromatic regions mediated by its binding specific repressive marks on tail histone H3, such trimethylated lysine 9 H3 (H3K9me3). However, whether epigenetic play an active role modulating material properties dictating emergent functions condensates, remains only partially understood. Here, we leverage reductionist system, comprised modified unmodified peptides, examine contribution behavior HP1α. We show presence peptides bearing H3K9me3 compatible while containing residues or transcriptional activation mark H3K4me3 are incompatible separation. In addition, inspired decreased ratio nuclear detected cells exposed uniaxial strain, using fluorescence microscopy rheological approaches demonstrate modulate dynamics network concentration dependent manner. These data suggest HP1α-DNA viscoelastic materials, whose may provide explanation for dynamic response mechanostimulation. Statement significance The genomic information eukaryotic necessitates compartmentalization into functional domains allowing expression identity-specific genes, repressing genes related alternative fates. Heterochromatin hosts these transcriptionally silent genome - which ensure stability identity -and characterized (H3K9m3) other specialized proteins (HP1a), shown separate DNA. HP1a forms persist peptides. nature depend H3K9me3:HP1 ratios, modulated mechanical strain cells. Thus, explain cells,

Язык: Английский

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Differential transcriptional profiles of vagal sensory neurons in female and male mice

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 20, 2024

Abstract The differences in metabolic homeostasis, diabetes, and obesity between males females are evident rodents humans. Vagal sensory neurons the vagus nerve ganglia innervate a variety of visceral organs use specialized endings to sense interoceptive signals. This organ-brain axis plays role relaying signals higher brain centers as well regulating vago-vagal reflex. I hypothesized that molecularly distinct populations vagal would result homeostasis sexes. Single-nucleus RNA sequencing analysis from reveals transcriptional profiles cells ganglia. These linked expression sex-specific genes such Xist, Tsix , Ddx3y . Among 13 neuronal clusters, one-fourth male mice located -enriched VN1 VN8 which display enrichment Trpv1, Piezo2, Htr3a Vip genes. In contrast, 70% found Xist clusters VN4, 6, 7, 10, 11, 13, show enriched Fgfr1, Lpar1, Cpe, Esr1, Nrg1, Egfr Oprm1 Two satellite identified, one contains some oligodendrocyte precursor cells. A small population express Ucp1 Plin1 indicating they epineural adipocytes. Understanding physiological consequences these transcriptomic on energy balance help develop treatments for dysregulation.

Язык: Английский

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Sustaining microglial reparative function enhances stroke recovery

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 13, 2024

Abstract Neurological symptoms after brain injury can remain as lifelong detrimental sequelae since most spontaneous recovery disappears within a few months injury. Microglia play an essential role in processes injury; however, cellular and molecular mechanisms that diminish functional unknown. We discovered by fate analysis reparative myeloid cells remained the post-stroke even losing their function. ZFP384 was identified pivotal transcriptional regulator diminished phase–associated gene expression cells, turning them into ruined which lost functions. YY1-mediated chromatin interaction necessary for expressing genes. Antisense oligonucleotide against Zfp384 sustained broad range of neural repair effects enhanced stroke recovery, chronic phase ischemic recovery. Thus, therapeutics preventing immunity from reaching state sustains

Язык: Английский

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