Genome access is transcription factor-specific and defined by nucleosome position

Molecular Cell, Год журнала: 2024, Номер 84(18), С. 3455 - 3468.e6

Опубликована: Авг. 28, 2024

Язык: Английский

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ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers

Nature Cell Biology, Год журнала: 2023, Номер 25(1), С. 42 - 55

Опубликована: Янв. 1, 2023

Язык: Английский

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Epigenetic biomarkers for animal welfare monitoring

Frontiers in Veterinary Science, Год журнала: 2023, Номер 9

Опубликована: Янв. 11, 2023

Biomarkers for holistic animal welfare monitoring represent a considerable unmet need in veterinary medicine. Epigenetic modifications, like DNA methylation, provide important information about cellular states and environments, which makes them highly attractive biomarker development. Up until now, much of the corresponding research has been focused on human cancers. However, increasing availability genomes epigenomes greatly improved our capacity epigenetic In this review, we an overview methylation patterns technologies that enable analysis these patterns. We also describe key frameworks compound biomarkers, clocks environment-specific signatures, allow complex, context-dependent readouts health disease. Finally, practical examples how biomarkers could be applied environmental exposure monitoring, two aspects assessments. Taken together, article provides molecular biological foundations development science their application potential monitoring.

Язык: Английский

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Orthologous transcription factor replacement reveals that stable TFIIIC complexes are required for proper mitotic chromosome segregation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Abstract Transcription factors are speculated to play crucial roles in adaptive evolution. Using ortholog replacement of essential transcription (eTFs) from other yeast species, we investigated how eTFs can change. Several orthologs could not fully complement Saccharomyces cerevisiae mutants, indicating that functions or interactions these have changed, rendering them incompatible. We further characterized TFIIIC, a fast-evolving protein complex assists RNA polymerase III-mediated transcription, which exhibited complete partial incompatibility several subunits. In the orthologous Tfc7-replacement line, binding TFIIIC tRNA genes was reduced, yet abundance severely affected. However, chromosomes cells were often mis-segregated during mitosis and their fitness reduced spindle checkpoint mutant. Our chromatin-immunoprecipitation experiments uncovered unstable results defective cohesion loading, leading chromosome mis-segregation. Swapping highly divergent C-terminal domain Tfc7 rescued its interaction with Tfc1 cell fitness, supporting is caused by altered between reveal distinct well-studied complex.

Язык: Английский

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Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders

iScience, Год журнала: 2025, Номер 28(3), С. 112092 - 112092

Опубликована: Фев. 22, 2025

The evolving field of neuroepigenetics provides important insights into the molecular foundations brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping epigenetic landscape during neurodevelopment disease. Traditional methods to investigate consequences chromatin-related provide valuable phenotypic but often lack information on biochemical mechanisms underlying these processes. Recent studies, however, are beginning elucidate how structural and/or functional aspects histone, DNA, RNA post-translational modifications affect transcriptional landscapes neurological phenotypes. Here, we review identification regulators from genomic studies disease, as well mechanistic findings that reveal intricacies neuronal chromatin regulation. We then discuss serve a guideline for future investigations. end by proposing roadmap therapies exploit coupling them recent advances targeted therapeutics.

Язык: Английский

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A comprehensive Schizosaccharomyces pombe atlas of physical transcription factor interactions with proteins and chromatin

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Transcription factors (TFs) are key regulators of gene expression, yet many their targets and modes action remain unknown. In Schizosaccharomyces pombe, one-third TFs solely homology predicted, with few experimentally validated. We created a comprehensive library 89 endogenously tagged S. pombe TFs, mapping protein chromatin interactions using immunoprecipitation-mass spectrometry immunoprecipitation sequencing. Our study identified interactors for half the over quarter potentially forming stable complexes. discovered DNA-binding sites most across 2,027 unique genomic regions, revealing motifs 38 uncovering complex network extensive TF cross- autoregulation. Characterization largest family revealed conserved DNA sequence preferences but diverse binding patterns repressive heterodimer, Ntu1/Ntu2, linked to perinuclear localization. TFexplorer webtool makes all data interactively accessible, offering insights into regulatory mechanisms broad biological relevance.

Язык: Английский

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Extensive N4 cytosine methylation is essential for Marchantia sperm function

Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

N4-methylcytosine (4mC) is an important DNA modification in prokaryotes, but its relevance and even presence eukaryotes have been mysterious. Here we show that spermatogenesis the liverwort Marchantia polymorpha involves two waves of extensive methylation reprogramming. First, 5-methylcytosine (5mC) expands from transposons to entire genome. Notably, second wave installs 4mC throughout genic regions, covering over 50% CG sites sperm. requires a methyltransferase (MpDN4MT1a) specifically expressed during late spermiogenesis. Deletion MpDN4MT1a alters sperm transcriptome, causes swimming fertility defects, impairs post-fertilization development. Our results reveal eukaryote, identify family eukaryotic methyltransferases, elucidate biological functions reproductive development, thereby expanding repertoire functional modifications.

Язык: Английский

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Dissecting reprogramming heterogeneity at single-cell resolution using scTF-seq

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

Опубликована: Фев. 2, 2024

Abstract Reprogramming approaches often produce heterogeneous cell fates and the mechanisms behind this heterogeneity are not well-understood. To address gap, we developed scTF-seq, a technique inducing single-cell barcoded doxycycline-inducible TF overexpression while quantifying dose-dependent transcriptomic changes. Applied to mouse embryonic multipotent stromal cells (MSCs), scTF-seq produced gain-of-function atlas for 384 murine TFs. This offers valuable resource gene regulation reprogramming research, identifying key TFs governing MSC lineage differentiation, cycle control, their interplay. Leveraging resolution, dissected along dose pseudotime. We thereby revealed stochastic fate branching, unveiling expression signatures that enhance our understanding prediction of efficiency. also allowed us classify into four sensitivity classes based on response determining features. Finally, in combinatorial observed same can exhibit both synergistic antagonistic effects another depending its dose. In summary, provides powerful tool gaining mechanistic insights how determine states, offering novel perspectives cellular engineering strategies.

Язык: Английский

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Atlas of cardiac endothelial cell enhancer elements linking the mineralocorticoid receptor to pathological gene expression

Science Advances, Год журнала: 2024, Номер 10(10)

Опубликована: Март 6, 2024

Endothelial cells play crucial roles in physiology and are increasingly recognized as therapeutic targets cardiovascular disease. Here, we analyzed the regulatory landscape of cardiac endothelial by assessing chromatin accessibility, histone modifications, 3D organization confirmed functional relevance enhancer-promoter interactions CRISPRi-mediated enhancer silencing. We used this dataset to explore mechanisms transcriptional regulation disease compared six different experimental models heart failure, hypertension, or diabetes. Enhancers that regulate gene expression diseased were enriched with binding sites for a distinct set transcription factors, including mineralocorticoid receptor (MR), known drug target failure hypertension. For proof concept, applied cell-specific MR deletion mice confirm MR-dependent predicted direct genes. Overall, have compiled here comprehensive atlas cell elements provides insight into role factors

Язык: Английский

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Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA

Current Opinion in Structural Biology, Год журнала: 2024, Номер 88, С. 102875 - 102875

Опубликована: Июль 10, 2024

Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially solvent-exposed near entry/exit sites, and frequently interact histones. The extent of TF-histone interactions, turn, depends on motif location nucleosome, type fold, adjacent domains present. interactions phase TF relative nucleosomes, we discuss how these complex surprisingly diverse between nucleosomes contribute function.

Язык: Английский

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