Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA200553 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR835926.fastq.gz | Fastqsanger.gz | |||
| SRR835927.fastq.gz | Fastqsanger.gz | |||
| SRR835928.fastq.gz | Fastqsanger.gz |
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Project description:A large portion of the mammalian genome is assembled into constitutive heterochromatin which is highly compact and transcriptionally silent throughout the cell cycle. On the molecular level it is characterized by DNA methylation, “repressive” histone marks (hypoacethylation, H3K9 trimethylation, H4K20 trimethylation) and the presence of heterochromatin protein 1 (HP1). Regions of constitutive heterochromatin such as telomeres, pericentromeres and centromeres play a critical role in the maintenance of the genome integrity. Using a technique called Proteomics of Isolated Chromatin Segments (PICh) we have identified SMCHD1 as a novel component of telomeres and pericentomeres. SMCHD1 was previously shown to be involved in the inactivaction of the X chromosome and imprinting, but the its exact role in these processes is not understood. Our study aims to unravel the role of SMCHD1 in the formation and/or maintenance of constitutive chromatin. Using human cancer cells as research model we are trying to discover its mechanism of action by identifying its interacting partners, characterizing its genome wide binding sites and characterizing the effect of SMCHD1 knockout on the heterochromatin function. Characterization of SMCHD1 binding sites in HCT-116 cells.
2015-05-01 | E-GEOD-46462 | biostudies-arrayexpress
Project description:A large portion of the mammalian genome is assembled into constitutive heterochromatin which is highly compact and transcriptionally silent throughout the cell cycle. On the molecular level it is characterized by DNA methylation, “repressive” histone marks (hypoacethylation, H3K9 trimethylation, H4K20 trimethylation) and the presence of heterochromatin protein 1 (HP1). Regions of constitutive heterochromatin such as telomeres, pericentromeres and centromeres play a critical role in the maintenance of the genome integrity. Using a technique called Proteomics of Isolated Chromatin Segments (PICh) we have identified SMCHD1 as a novel component of telomeres and pericentomeres. SMCHD1 was previously shown to be involved in the inactivaction of the X chromosome and imprinting, but the its exact role in these processes is not understood. Our study aims to unravel the role of SMCHD1 in the formation and/or maintenance of constitutive chromatin. Using human cancer cells as research model we are trying to discover its mechanism of action by identifying its interacting partners, characterizing its genome wide binding sites and characterizing the effect of SMCHD1 knockout on the heterochromatin function.
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Project description:Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) is an SMC-like protein that plays an important role in X chromosome inactivation and is mutated in two human diseases, a muscular dystrophy, and a rare developmental disorder. Here we characterized the function of SMCHD1 in human myoblasts and focused on its role on autosomes. We found that SMCHD1 colocalizes with Lamin B1 and the constitutive heterochromatin mark H3K9me3. Loss of SMCHD1 leads to a loss of heterochromatin at nuclear lamina regions and to extensive changes of the epigenome on most chromosomes. In SMCHD1-deficient cells, about half the regions that normally bind SMCHD1 loose H3K9me3, acquire long stretches of DNA hypermethylation and gain a variety of active chromatin marks including H3K4me3, H3K4me1, histone H3K27 acetylation, and H3K36 di- and trimethylation. Three-dimensional chromatin analysis using HiC shows that long range contacts between different heterochromatin blocks (B compartments) on the same chromosome are diminished while there is extensive formation of new topologically associated domains (TADs) and loops anchored at newly created CTCF/RAD21 binding sites. Inactivation of SMCHD1 promotes many inactive (B) to active (A) compartment transitions. These transitions are accompanied by activation of about 200 previously silenced genes with potential implications for the etiology and progression of SMCHD1-linked diseases. Our data suggest that SMCHD1 functions as a genome compartment organizer and as an important anchor for heterochromatin domains at the nuclear lamina ensuring that lamina- associated domains are protected from histone and DNA modification enzymes that typically operate in active chromatin.
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Project description:Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) is an SMC-like protein that plays an important role in X chromosome inactivation and is mutated in two human diseases, a muscular dystrophy, and a rare developmental disorder. Here we characterized the function of SMCHD1 in human myoblasts and focused on its role on autosomes. We found that SMCHD1 colocalizes with Lamin B1 and the constitutive heterochromatin mark H3K9me3. Loss of SMCHD1 leads to a loss of heterochromatin at nuclear lamina regions and to extensive changes of the epigenome on most chromosomes. In SMCHD1-deficient cells, about half the regions that normally bind SMCHD1 loose H3K9me3, acquire long stretches of DNA hypermethylation and gain a variety of active chromatin marks including H3K4me3, H3K4me1, histone H3K27 acetylation, and H3K36 di- and trimethylation. Three-dimensional chromatin analysis using HiC shows that long range contacts between different heterochromatin blocks (B compartments) on the same chromosome are diminished while there is extensive formation of new topologically associated domains (TADs) and loops anchored at newly created CTCF/RAD21 binding sites. Inactivation of SMCHD1 promotes many inactive (B) to active (A) compartment transitions. These transitions are accompanied by activation of about 200 previously silenced genes with potential implications for the etiology and progression of SMCHD1-linked diseases. Our data suggest that SMCHD1 functions as a genome compartment organizer and as an important anchor for heterochromatin domains at the nuclear lamina ensuring that lamina- associated domains are protected from histone and DNA modification enzymes that typically operate in active chromatin.
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Project description:Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) is an SMC-like protein that plays an important role in X chromosome inactivation and is mutated in two human diseases, a muscular dystrophy, and a rare developmental disorder. Here we characterized the function of SMCHD1 in human myoblasts and focused on its role on autosomes. We found that SMCHD1 colocalizes with Lamin B1 and the constitutive heterochromatin mark H3K9me3. Loss of SMCHD1 leads to a loss of heterochromatin at nuclear lamina regions and to extensive changes of the epigenome on most chromosomes. In SMCHD1-deficient cells, about half the regions that normally bind SMCHD1 loose H3K9me3, acquire long stretches of DNA hypermethylation and gain a variety of active chromatin marks including H3K4me3, H3K4me1, histone H3K27 acetylation, and H3K36 di- and trimethylation. Three-dimensional chromatin analysis using HiC shows that long range contacts between different heterochromatin blocks (B compartments) on the same chromosome are diminished while there is extensive formation of new topologically associated domains (TADs) and loops anchored at newly created CTCF/RAD21 binding sites. Inactivation of SMCHD1 promotes many inactive (B) to active (A) compartment transitions. These transitions are accompanied by activation of about 200 previously silenced genes with potential implications for the etiology and progression of SMCHD1-linked diseases. Our data suggest that SMCHD1 functions as a genome compartment organizer and as an important anchor for heterochromatin domains at the nuclear lamina ensuring that lamina- associated domains are protected from histone and DNA modification enzymes that typically operate in active chromatin.
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Project description:Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) is an SMC-like protein that plays an important role in X chromosome inactivation and is mutated in two human diseases, a muscular dystrophy, and a rare developmental disorder. Here we characterized the function of SMCHD1 in human myoblasts and focused on its role on autosomes. We found that SMCHD1 colocalizes with Lamin B1 and the constitutive heterochromatin mark H3K9me3. Loss of SMCHD1 leads to a loss of heterochromatin at nuclear lamina regions and to extensive changes of the epigenome on most chromosomes. In SMCHD1-deficient cells, about half the regions that normally bind SMCHD1 loose H3K9me3, acquire long stretches of DNA hypermethylation and gain a variety of active chromatin marks including H3K4me3, H3K4me1, histone H3K27 acetylation, and H3K36 di- and trimethylation. Three-dimensional chromatin analysis using HiC shows that long range contacts between different heterochromatin blocks (B compartments) on the same chromosome are diminished while there is extensive formation of new topologically associated domains (TADs) and loops anchored at newly created CTCF/RAD21 binding sites. Inactivation of SMCHD1 promotes many inactive (B) to active (A) compartment transitions. These transitions are accompanied by activation of about 200 previously silenced genes with potential implications for the etiology and progression of SMCHD1-linked diseases. Our data suggest that SMCHD1 functions as a genome compartment organizer and as an important anchor for heterochromatin domains at the nuclear lamina ensuring that lamina- associated domains are protected from histone and DNA modification enzymes that typically operate in active chromatin.
2025-06-27 | GSE251749 | GEO
Project description:Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) is an SMC-like protein that plays an important role in X chromosome inactivation and is mutated in two human diseases, a muscular dystrophy, and a rare developmental disorder. Here we characterized the function of SMCHD1 in human myoblasts and focused on its role on autosomes. We found that SMCHD1 colocalizes with Lamin B1 and the constitutive heterochromatin mark H3K9me3. Loss of SMCHD1 leads to a loss of heterochromatin at nuclear lamina regions and to extensive changes of the epigenome on most chromosomes. In SMCHD1-deficient cells, about half the regions that normally bind SMCHD1 loose H3K9me3, acquire long stretches of DNA hypermethylation and gain a variety of active chromatin marks including H3K4me3, H3K4me1, histone H3K27 acetylation, and H3K36 di- and trimethylation. Three-dimensional chromatin analysis using HiC shows that long range contacts between different heterochromatin blocks (B compartments) on the same chromosome are diminished while there is extensive formation of new topologically associated domains (TADs) and loops anchored at newly created CTCF/RAD21 binding sites. Inactivation of SMCHD1 promotes many inactive (B) to active (A) compartment transitions. These transitions are accompanied by activation of about 200 previously silenced genes with potential implications for the etiology and progression of SMCHD1-linked diseases. Our data suggest that SMCHD1 functions as a genome compartment organizer and as an important anchor for heterochromatin domains at the nuclear lamina ensuring that lamina- associated domains are protected from histone and DNA modification enzymes that typically operate in active chromatin.
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Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature