Nucleosome

Gene activity is tightly controlled by reversible chemical modifications called epigenetic marks, which are of various types and modulate gene accessibility without affecting the DNA sequence. Despite an increasing body of evidence demonstrating the role of oxidative-type modifications of histones in gene expression regulation, there remains a complete absence of structural data at the atomistic level to understand the molecular mechanisms behind their regulatory action. Owing to μs time-scale MD simulations and protein communication networks analysis, we describe the impact of histone H3 hyperoxidation (i...

The PhiC31 integration system allows for targeted and efficient transgene integration and expression by recognizing pseudo attP sites in mammalian cells and integrating the exogenous genes into the open chromatin regions of active chromatin. In order to investigate the regulatory patterns of efficient gene expression in the open chromatin region of PhiC31 integration, this study utilized Ubiquitous Chromatin Opening Element (UCOE) and activating RNA (saRNA) to modulate the chromatin structure in the promoter region of the PhiC31 integration vector...

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Histone H1 is involved in chromatin compaction and dynamics. In human cells, the H1 complement is formed by different amounts of somatic H1 subtypes, H1.0-H1.5 and H1X. The amount of each variant depends on the cell type, the cell cycle phase, and the time of development and can be altered in disease. However, the mechanisms regulating H1 protein levels have not been described. We have analyzed the contribution of the proteasome to the degradation of H1 subtypes in human cells using two different inhibitors: MG132 and bortezomib...

Nucleosome assembly proteins (NAPs) have been identified as histone chaperons. Testis-Specific Protein, Y-Encoded-Like (TSPYL) is a newly arisen NAP family in mammals. TSPYL2 can be transcriptionally induced by DNA damage and TGFβ causing proliferation arrest. TSPYL1, another TSPYL family member, has been poorly characterized and is the only TSPYL family member known to be causal of a lethal recessive disease in humans. This study shows that TSPYL1 and TSPYL2 play an opposite role in TGFβ signaling...

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well-known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae , the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). We have previously reported that in the absence of SIR2 , a derepressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy...

Identifying causal variants among tens or hundreds of associated variants at each locus mapped by genome-wide association studies (GWAS) of complex traits is a challenge. As vast majority of GWAS variants are noncoding, sequence variation at cis -regulatory elements affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this cis -regulatory hypothesis and combining it with the observation that nucleosome-free open chromatin is a universal hallmark of all types of cis -regulatory elements, we aimed to identify candidate causal regulatory variants underlying electrocardiographic QT interval GWAS loci...

Apicomplexan parasites have complex life cycles, often requiring transmission between two different hosts, facing periods of dormancy within the host or in the environment to maximize chances of transmission. To support survival in these different conditions, tightly regulated and correctly timed gene expression is critical. The modification of histones and nucleosome composition makes a significant contribution to this regulation, and as eukaryotes, the fundamental mechanisms underlying this process in apicomplexans are similar to those in model eukaryotic organisms...

Histone chaperones serve a pivotal role in maintaining human physiological processes. They interact with histones in a stable manner, ensuring the accurate and efficient execution of DNA replication, repair and transcription. Retinoblastoma binding protein (RBBP)4 and RBBP7 represent a crucial pair of histone chaperones, which not only govern the molecular behavior of histones H3 and H4, but also participate in the functions of several protein complexes, such as polycomb repressive complex 2 and nucleosome remodeling and deacetylase, thereby regulating the cell cycle, histone modifications, DNA damage and cell fate...

As a well-conserved histone variant, H2A.Z epigenetically regulates plant growth and development as well as the interaction with environmental factors. However, the role of H2A.Z in response to salt stress remains unclear, and whether nucleosomal H2A.Z occupancy work on the gene responsiveness upon salinity is obscure. Here, we elucidate the involvement of H2A.Z in salt response by analysing H2A.Z disorder plants with impaired or overloaded H2A.Z deposition. The salt tolerance is dramatically accompanied by H2A...

Hepatitis B virus (HBV) infection poses a significant burden on global public health. Unfortunately, current treatments cannot fully alleviate this burden as they have limited effect on the transcriptional activity of the tenacious covalently closed circular DNA (cccDNA) responsible for viral persistence. Consequently, the HBV life cycle should be further investigated to develop new anti-HBV pharmaceutical targets. Our previous study discovered that the host gene TMEM203 hinders HBV replication by participating in calcium ion regulation...

ATP dependent chromatin remodelers have pivotal roles in transcription, DNA replication and repair, and maintaining genome integrity. SWI/SNF remodelers were first discovered in yeast genetic screens for factors involved in mating type switching or for using alternative energy sources therefore termed SWI/SNF complex (short for SWItch/Sucrose NonFermentable). The SWI/SNF complexes utilize energy from ATP hydrolysis to disrupt histone-DNA interactions and shift, eject, or reposition nucleosomes making the underlying DNA more accessible to specific transcription factors and other regulatory proteins...

Histone chaperones-structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)-protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation...

Genome-wide identification of chromatin organization and structure has been generally probed by measuring accessibility of the underlying DNA to nucleases or methyltransferases. These methods either only observe the positioning of a single nucleosome or rely on large enzymes to modify or cleave the DNA. We developed adduct sequencing (Add-seq), a method to probe chromatin accessibility by treating chromatin with the small molecule angelicin, which preferentially intercalates into DNA not bound to core nucleosomes...

During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch...

LSD1 histone H3K4 demethylase and its binding partner PHF21A, a reader protein for unmethylated H3K4, both undergo neuron-specific microexon splicing. The LSD1 neuronal microexon weakens H3K4 demethylation activity and can alter the substrate specificity to H3K9 or H4K20. Meanwhile, the PHF21A neuronal microexon interferes with nucleosome binding. However, the temporal expression patterns of LSD1 and PHF21A splicing isoforms during brain development remain unknown. In this work, we report that neuronal PHF21A isoform expression precedes neuronal LSD1 isoform expression during human neuron differentiation and mouse brain development...

BACKGROUND: Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. RESULTS: We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma...

Cancer stem cells (CSCs) were first discovered in the 1990s, revealing the mysteries of cancer origin, migration, recurrence and drug-resistance from a new perspective. The expression of pluripotent genes and complex signal regulatory networks are significant features of CSC, also act as core factors to affect the characteristics of CSC. Transcription is a necessary link to regulate the phenotype and potential of CSC, involving chromatin environment, nucleosome occupancy, histone modification, transcription factor (TF) availability and cis-regulatory elements, which suffer from ambient pressure...

Nucleosome, the building block of chromatin, plays pivotal roles in all DNA-related processes. While cryogenic-electron microscopy (cryo-EM) has significantly advanced our understanding of nucleosome structures, the emerging field of single-molecule force spectroscopy is illuminating their dynamic properties. This technique is crucial for revealing how nucleosome behavior is influenced by chaperones, remodelers, histone variants, and post-translational modifications, particularly in their folding and unfolding mechanisms under tension...

Spn1 is a multifunctional histone chaperone essential for life in eukaryotes. While previous work has elucidated regions of the protein important for its many interactions, it is unknown how these domains contribute to the maintenance of chromatin structure. Here, we employ digestion by micrococcal nuclease followed by single-stranded library preparation and sequencing (MNase-SSP) to characterize chromatin structure in yeast expressing wild-type or mutants of Spn1. We mapped nucleosome and subnucleosomal protections genome-wide, and surprisingly, we observed a genome-wide loss of subnucleosomal protection over nucleosome-depleted regions (NDRs) in the Spn1-K192N-containing strain, indicating critical functions of Spn1 in maintaining normal chromatin architecture in promoter regions...