Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10412 (H1.4)
 75 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HRas mutation rate is high in gastric cancer while the deep mechanism of HRas's oncogenic effects is unclear. The current work designed to link HRas signaling with H1.4S27ph in gastric cancer to decode the unclear mechanism in epigenetics standpoint. RasQ61R/T35S expressing plasmids were transfected into SNU-16 cells. Western blot was conducted to check H1.4S27ph and extracellular-signal-regulated kinase 1/2 (ERK1/2) expression. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, colony formation, and transwell assays were carried out to see the effects of H1.4S27ph on SNU-16 cells phenotype. Chromatin immunoprecipitation was utilized to detect the interaction between H1.4S27ph and Ras downstream genes. Further, the enzymes responsible for H1.4S27 phosphorylation were studied by a quantitative reverse transcription-polymerase chain reaction and western blot. Ras mutation repressed H1.4 phosphorylation at Ser27 accompanied by ERK1/2 activation. H1.4S27ph reduced SNU-16 cells viability, colony formation, and migration. Meanwhile, H1.4S27ph regulated the transcription of Ras downstream genes. Ras-ERK1/2 signaling inhibited H1.4S27ph via inhibiting the activity of Aurora B. Aurora B exhibited H1.4S27ph-like effects on inhibiting SNU-16 cells viability, migration, and S-phase arrest. Further, Ras-ERK1/2 signaling degenerated Aurora B via mediating MDM2. H1.4S27ph worked as an anti-gastric cancer factor. It can be inhibited by activation of Ras-ERK1/2 signaling. Ras-ERK1/2 signaling repressed H1.4S27ph via MDM2-dependent degradation of Aurora B.
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PMID:Ras-ERK1/2 signaling participates in the progression of gastric cancer through repressing Aurora B-mediated H1.4 phosphorylation at Ser27. 3190 25

Human linker histones (H1s) are important in chromatin packaging and condensation. The central globular domain of H1 anchors the protein to the nucleosome. The nucleosomal binding modes of different H1 globular domains may affect nucleosomal DNA accessibility in distinct ways. The globular domain structures of human linker histones H1.0 (GH1.0), H1.4 (GH1.4), H1t (GH1t) and H1oo (GH1oo) were homology modelled and energy minimized. A docking algorithm [validated by re-docking GH5 from the GH5-chromatosome crystal structure (PDB: 4QLC) to the nucleosome] was used to dock the modelled domains to the same nucleosome template. In addition, GH1 (PDB: 1GHC) and a protein consisting of the N-terminal and globular domains of H1x (NGH1x) were also docked using this algorithm. Models of these docked structures are presented here in the form of PDB files. The models can be used to gain more insight with regards to the nucleosomal binding modes of H1s and their individual influence on chromatin compaction.
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PMID:Docking data of selected human linker histone variants to the nucleosome. 3233 29

Neutrophils are important innate immune cells that tackle invading pathogens with different effector mechanisms. They acquire this antimicrobial potential during their maturation in the bone marrow, where they differentiate from hematopoietic stem cells in a process called granulopoiesis. Mature neutrophils are terminally differentiated and short-lived with a high turnover rate. Here, we show a critical role for linker histone H1 on the differentiation and function of neutrophils using a genome-wide CRISPR/Cas9 screen in the human cell line PLB-985. We systematically disrupted expression of somatic H1 subtypes to show that individual H1 subtypes affect PLB-985 maturation in opposite ways. Loss of H1.2 and H1.4 induced an eosinophil-like transcriptional program, thereby negatively regulating the differentiation into the neutrophil lineage. Importantly, H1 subtypes also affect neutrophil differentiation and the eosinophil-directed bias of murine bone marrow stem cells, demonstrating an unexpected subtype-specific role for H1 in granulopoiesis.
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PMID:Linker histone H1.2 and H1.4 affect the neutrophil lineage determination. 3239 89

Squamous cell carcinoma of the head and neck (SCCHN) is a malignancy with poor outcomes, thus novel therapies are urgently needed. We recently showed that WHSC1 is necessary for the viability of SCCHN cells through H3K36 di-methylation. Here, we report the identification of its novel substrate, histone H1, and that WHSC1-mediated H1.4K85 mono-methylation may enhance stemness features in SCCHN cells. To identify proteins interacting with WHSC1 in SCCHN cells, WHSC1 immunoprecipitation and mass spectrometry identified H1 as a WHSC1-interacting candidate. In vitro methyltransferase assays showed that WHSC1 mono-methylates H1 at K85. We generated an H1K85 mono-methylation-specific antibody and confirmed that this methylation occurs in vivo. Sphere formation assays using SCC-35 cells stably expressing either wild-type (FLAG-H1.4-WT) or mutated (FLAG-H1.4K85A) vector with lysine 85 to alanine substitution which is not methylated, indicated a higher number of spheres in SCC-35 cells expressing the wild type than those with the mutant vector. SCC-35 cells expressing the wild type H1.4 proliferated faster than those expressing the mutated vector. RNA sequencing, RT-PCR and Western blotting of the FLAG-H1.4-WT or FLAG-H1.4K85A SCC-35 cells revealed that OCT4 levels were higher in wild type compared to mutant cells. These results were reproduced in SCC-35 cells genetically modified with CRISPR to express H1.4K85R. Chromatin immunoprecipitation showed that FLAG-H1.4K85A had decreased occupancy in the OCT4 gene compared to FLAG-H1.4-WT. This study supports that WHSC1 mono-methylates H1.4 at K85, it induces transcriptional activation of OCT4 and stemness features in SCCHN cells, providing rationale to target H1.4K85 mono-methylation through WHSC1 in SCCHN.
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PMID:WHSC1 monomethylates histone H1 and induces stem-cell like features in squamous cell carcinoma of the head and neck. 3249 98

Core histone variants, such as H2A.X and H3.3, serve specialized roles in chromatin processes that depend on the genomic distributions and amino acid sequence differences of the variant proteins. Modifications of these variants alter interactions with other chromatin components and thus the protein's functions. These inferences add to the growing arsenal of evidence against the older generic view of those linker histones as redundant repressors. Furthermore, certain modifications of specific H1 variants can confer distinct roles. On the one hand, it has been reported that the phosphorylation of H1 results in its release from chromatin and the subsequent transcription of HIV-1 genes. On the other hand, recent evidence indicates that phosphorylated H1 may in fact be associated with active promoters. This conflict suggests that different H1 isoforms and modified versions of these variants are not redundant when together but may play distinct functional roles. Here, we provide the first genome-wide evidence that when phosphorylated, the H1.4 variant remains associated with active promoters and may even play a role in transcription activation. Using novel, highly specific antibodies, we generated the first genome-wide view of the H1.4 isoform phosphorylated at serine 187 (pS187-H1.4) in estradiol-inducible MCF7 cells. We observe that pS187-H1.4 is enriched primarily at the transcription start sites (TSSs) of genes activated by estradiol treatment and depleted from those that are repressed. We also show that pS187-H1.4 associates with 'early estrogen response' genes and stably interacts with RNAPII. Based on the observations presented here, we propose that phosphorylation at S187 by CDK9 represents an early event required for gene activation. This event may also be involved in the release of promoter-proximal polymerases to begin elongation by interacting directly with the polymerase or other parts of the transcription machinery. Although we focused on estrogen-responsive genes, taking into account previous evidence of H1.4's enrichment of promoters of pluripotency genes, and its involvement with rDNA activation, we propose that H1.4 phosphorylation for gene activation may be a more global observation.
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PMID:Site-Specific Phosphorylation of Histone H1.4 Is Associated with Transcription Activation. 3323 24


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