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

Previous studies have shown two homologous chromodomain modules in the HP1 and Polycomb proteins exhibit discriminatory binding to related methyllysine residues (embedded in ARKS motifs) of the histone H3 tail. Methylated ARK(S/T) motifs have recently been identified in other chromatin factors (e.g. linker histone H1.4 and lysine methyltransferase G9a). These are thought to function as peripheral docking sites for the HP1 chromodomain. In vertebrates, HP1-like chromodomains are also present in the chromodomain Y chromosome (CDY) family of proteins adjacent to a putative catalytic motif. The human genome encodes three CDY family proteins, CDY, CDYL, and CDYL2. These have putative functions ranging from establishment of histone H4 acetylation during spermiogenesis to regulation of transcription co-repressor complexes. To delineate the biochemical functions of the CDY family chromodomains, we analyzed their specificity of methyllysine recognition. We detected substantial differences among these factors. The CDY chromodomain exhibits discriminatory binding to lysine-methylated ARK(S/T) motifs, whereas the CDYL2 chromodomain binds with comparable strength to multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL chromodomain prohibit such binding interactions in vitro and in vivo. However, point mutations can rescue binding. In support of the in vitro binding properties of the chromodomains, the full-length CDY family proteins exhibit substantial variability in chromatin localization. Our studies underscore the significance of subtle sequence differences in a conserved signaling module for diverse epigenetic regulatory pathways.
 ...
PMID:Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. 1845 Jul 45

At least six histone H1 variants exist in somatic mammalian cells that bind to the linker DNA and stabilize the nucleosome particle contributing to higher order chromatin compaction. In addition, H1 seems to be actively involved in the regulation of gene expression. However, it is not well known whether the different variants have distinct roles or if they regulate specific promoters. We have explored this by inducible shRNA-mediated knock-down of each of the H1 variants in a human breast cancer cell line. Rapid inhibition of each H1 variant was not compensated for by changes of expression of other variants. Microarray experiments have shown a different subset of genes to be altered in each H1 knock-down. Interestingly, H1.2 depletion caused specific effects such as a cell cycle G1-phase arrest, the repressed expression of a number of cell cycle genes, and decreased global nucleosome spacing. On its side, H1.4 depletion caused cell death in T47D cells, providing the first evidence of the essential role of an H1 variant for survival in a human cell type. Thus, specific phenotypes are observed in breast cancer cells depleted of individual histone H1 variants, supporting the theory that distinct roles exist for the linker histone variants.
 ...
PMID:Depletion of human histone H1 variants uncovers specific roles in gene expression and cell growth. 1892 31

The linker histone H1 generally participates in the establishment of chromatin structure. However, of the seven somatic H1 isotypes in humans some are also implicated in the regulation of local gene expression. Histone H1 isotype 4 (H1.4) represses transcription, and its lysine residue 26 (Lys(26)) was found to be important in this aspect. H1.4K26 is known to be methylated and acetylated in vivo, but the enzymes responsible for these post-translational modifications and the regulatory cues that promote H1.4 residence on chromatin are poorly characterized. Here we report that the euchromatic histone lysine methyltransferase G9a/KMT1C mediates H1.4K26 mono- and dimethylation in vitro and in vivo and thereby provides a recognition surface for the chromatin-binding proteins HP1 and L3MBTL1. Moreover, we show evidence that G9a promotes H1 deposition and is required for retention of H1 on chromatin. We also identify members of the JMJD2/KDM4 subfamily of jumonji-C type histone demethylases as being responsible for the removal of H1.4K26 methylation.
 ...
PMID:Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins. 1914 45

Linker histones H1 are key modulators of chromatin structure. Tightness of their binding to DNA is regulated by posttranslational modifications. In this study we have analyzed posttranslational modifications of five major variants of H1 in human tissue - H1.0, H1.2, H1.3, H1.4, and H1.5. To improve sequence coverage, tryptic peptides of H1 were separated by HPLC and the individual fractions were analyzed using a peptide on-chip implementation of nanoelectrospray (TriVersa), coupled to a linear ion trap-orbitrap hybrid instrument. For quantitative analysis of lysine methylation, ionization efficiencies of methylated and nonmethylated peptides were determined using synthetic peptides. Our analysis revealed that monomethylation of lysine residues alongside with phosphorylation of serine and threonine residues is the major modification of H1 in tissue. We found that most prominent methylation sites are in the N-terminal tail and the globular domain of H1. In the C- terminal domains we identified only few and less abundant methylation sites. Quantitative analysis revealed that up to 25% of H1.4 is methylated at K-26 in human tissues. Another prominent methylation site was mapped to K-27 in H1.5, which resembles the K-26 site in H1.4. In H1.0 five less abundant (<1% of H1.0) sites were identified. Analysis of patient matched pairs of cancer and adjacent normal breast demonstrated high variation in H1 methylation between individuals.
 ...
PMID:Mapping of lysine monomethylation of linker histones in human breast and its cancer. 1955 82

Although ubiquitously present in chromatin, the function of the linker histone subtypes is partly unknown and contradictory studies on their properties have been published. To explore whether the various H1 subtypes have a differential role in the organization and dynamics of chromatin we have incorporated all of the somatic human H1 subtypes into minichromosomes and compared their influence on nucleosome spacing, chromatin compaction and ATP-dependent remodeling. H1 subtypes exhibit different affinities for chromatin and different abilities to promote chromatin condensation, as studied with the Atomic Force Microscope. According to this criterion, H1 subtypes can be classified as weak condensers (H1.1 and H1.2), intermediate condensers (H1.3) and strong condensers (H1.0, H1.4, H1.5 and H1x). The variable C-terminal domain is required for nucleosome spacing by H1.4 and is likely responsible for the chromatin condensation properties of the various subtypes, as shown using chimeras between H1.4 and H1.2. In contrast to previous reports with isolated nucleosomes or linear nucleosomal arrays, linker histones at a ratio of one per nucleosome do not preclude remodeling of minichromosomes by yeast SWI/SNF or Drosophila NURF. We hypothesize that the linker histone subtypes are differential organizers of chromatin, rather than general repressors.
 ...
PMID:Histone H1 subtypes differentially modulate chromatin condensation without preventing ATP-dependent remodeling by SWI/SNF or NURF. 1979 10

The potential for adverse health effects of using tungsten and its alloys in military munitions are an important concern to both civilians and the US military. The toxicological implications of exposure to tungsten, its alloys, and the soluble tungstate (Na(2)WO(4)) are currently under investigation. To examine tungstate toxicity, a series of experiments to determine its in vitro effects on cells of the immune system were performed. We identified alterations in isolated human peripheral blood lymphocytes (PBL) treated in vitro with sodium tungstate (0.01, 0.1, 1.0, and 10 mM). Analyses of apoptosis with annexin V and propidium iodide revealed a dose- and time-dependent increase in the quantity of cells in early apoptosis after tungstate exposure. Reductions in the number of cells entering into the cell cycle were also noted. Exposure of PBL to tungstate (1 mM) and Concanavalin A (ConA) for 72 h reduced the number of cells in S and G(2)/M phases of the cell cycle. There were alterations in the numbers of cells in G(0)/G(1), S, and G(2)/M phases of the cell cycle in long-term THP-1 (acute leukemic monocytes) cultures treated with tungstate (0.01, 0.1, 1.0, and 10 mM). Gel electrophoresis, silver staining, and LC-MS/MS showed the cytoplasmic presence of histone H1b and H1d after 72 h of tungstate exposure. The addition of tungstate to cultures resulted in significant reductions in the quantity of interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and IL-6 produced by stimulated [CD3/CD28, ConA, or lipopolysaccharide (LPS)] and tungstate-treated lymphocytes. Taken together, these data indicate that tungstate increases apoptosis of PBL, alters cell cycle progression, reduces cytokine production, and therefore warrants further investigation.
 ...
PMID:Sodium tungstate (Na2WO4) exposure increases apoptosis in human peripheral blood lymphocytes. 2017 56

Histone H1 phosphorylation affects chromatin condensation and function, but little is known about how specific phosphorylations impact the function of H1 variants in higher eukaryotes. In this study, we show that specific sites in H1.2 and H1.4 of human cells are phosphorylated only during mitosis or during both mitosis and interphase. Antisera generated to individual H1.2/H1.4 interphase phosphorylations reveal that they are distributed throughout nuclei and enriched in nucleoli. Moreover, interphase phosphorylated H1.4 is enriched at active 45S preribosomal RNA gene promoters and is rapidly induced at steroid hormone response elements by hormone treatment. Our results imply that site-specific interphase H1 phosphorylation facilitates transcription by RNA polymerases I and II and has an unanticipated function in ribosome biogenesis and control of cell growth. Differences in the numbers, structure, and locations of interphase phosphorylation sites may contribute to the functional diversity of H1 variants.
 ...
PMID:Histone H1 phosphorylation is associated with transcription by RNA polymerases I and II. 2043 94

Histone H1 is commonly used to assay kinase activity in vitro. As many promising targeted therapies affect kinase activity of specific enzymes involved in cancer transformation, H1 phosphorylation can serve as potential pharmacodynamic marker for drug activity within the cell. In this study we utilized a phosphoproteomic workflow to characterize histone H1 phosphorylation changes associated with two targeted therapies in the Kasumi-1 acute myeloid leukemia cell line. The phosphoproteomic workflow was first validated with standard casein phosphoproteins and then applied to the direct analysis of histone H1 from Kasumi-1 nuclear lysates. Ten H1 phosphorylation sites were identified on the H1 variants, H1.2, H1.3, H1.4, H1.5 and H1.x. LC MS profiling of intact H1s demonstrated global dephosphorylation of H1.5 associated with therapy by the cyclin-dependent kinase inhibitor, flavopiridol and the Heat Shock Protein 90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin. In contrast, independent treatments with a nucleotide analog, proteosome inhibitor and histone deacetylase inhibitor did not exhibit decreased H1.5 phosphorylation. The data presented herein demonstrate that potential of histones to assess the cellular response of reagents that have direct and indirect effects on kinase activity that alters histone phosphorylation. As such, this approach may be a highly informative marker for response to targeted therapies influencing histone phosphorylation.
 ...
PMID:Assaying pharmacodynamic endpoints with targeted therapy: flavopiridol and 17AAG induced dephosphorylation of histone H1.5 in acute myeloid leukemia. 2111 Mar 23

The linker histone H1 plays an essential role in maintaining and establishing higher-order chromatin structure. As with core histones, histone H1 is also extensively covalently modified. We showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27. We demonstrate that histone H1.4 is the only somatic linker histone variant targeted by Aurora B and that Aurora B exclusively phosphorylates S27. Adjacent K26 dimethylation can regulate Aurora B activity towards S27, uncovering a crosstalk between these modifications. Finally, our fluorescence recovery after photobleaching (FRAP) analysis on histone H1.4 mutants suggests a role of S27 phosphorylation in the regulation of histone H1.4 mobility and chromatin binding in mitosis.
 ...
PMID:Isoform-specific phosphorylation of human linker histone H1.4 in mitosis by the kinase Aurora B. 2151 33

Global histone H1 phosphorylation correlates with cell cycle progression. However, the function of site-specific H1 variant phosphorylation remains unclear. Our mass spectrometry analysis revealed a novel N-terminal phosphorylation of the major H1 variant H1.4 at serine 35 (H1.4S35ph), which accumulates at mitosis immediately after H3 phosphorylation at serine 10. Protein kinase A (PKA) was found to be a kinase for H1.4S35. Importantly, Ser-35-phosphorylated H1.4 dissociates from mitotic chromatin. Moreover, H1.4S35A substitution mutant cannot efficiently rescue the mitotic defect following H1.4 depletion, and inhibition of PKA activity increases the mitotic chromatin compaction depending on H1.4. Our results not only indicate that PKA-mediated H1.4S35 phosphorylation dissociates H1.4 from mitotic chromatin but also suggest that this phosphorylation is necessary for specific mitotic functions.
 ...
PMID:Protein kinase A-mediated serine 35 phosphorylation dissociates histone H1.4 from mitotic chromosome. 2185 32


<< Previous 1 2 3 4 5 6 7 8 Next >>