Macrocycle Based Chemoproteomic Profiling of HTT HAP40 Interaction Networks
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Rachel Harding
PROVIDER: MSV000100395 | MassIVE | Wed Jan 07 08:45:00 GMT 2026
REPOSITORIES: MassIVE
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Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.
2013-05-03 | E-GEOD-34721 | biostudies-arrayexpress
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion.
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Project description:Proteomic methods for RNA interactome capture (RIC) rely principally on crosslinking native or labeled cellular RNA to enrich and investigate RNA-binding protein (RBP) composition and function in cells. The ability to measure RBP activity at individual binding sites by RIC, however, has been more challenging due to the heterogenous nature of peptide adducts derived from the RNA-protein crosslinked site. Here, we present an orthogonal strategy that utilizes clickable electrophilic purines to directly quantify protein-RNA interactions on proteins through photoaffinity competition with 4-thiouridine (4SU)-labeled RNA in cells. Our photo-activatable-competition and chemoproteomic enrichment (PACCE) method facilitated detection of >5,500 cysteine sites across ~3,000 proteins displaying RNA-sensitive alterations in probe binding. Importantly, PACCE enabled functional profiling of canonical RNA-binding domains as well as discovery of moonlighting RNA binding activity in the human proteome. Collectively, we present a chemoproteomic platform for global quantification of protein-RNA binding activity in living cells.
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Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the liver of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
2016-02-15 | E-GEOD-65771 | biostudies-arrayexpress
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the striatum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
2016-02-15 | E-GEOD-65773 | biostudies-arrayexpress
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the liver of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
2016-02-15 | E-GEOD-65772 | biostudies-arrayexpress
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the striatum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
2016-02-15 | E-GEOD-65774 | biostudies-arrayexpress
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the hippocampus of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
2015-11-03 | E-GEOD-73503 | biostudies-arrayexpress
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals. miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the cerebellum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
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Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals. miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the hippocampus of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.
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