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Article ; Online: A CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease.

Aldous, Sarah G / Smith, Edward J / Landles, Christian / Osborne, Georgina F / Cañibano-Pico, Maria / Nita, Iulia M / Phillips, Jemima / Zhang, Yongwei / Jin, Bo / Hirst, Marissa B / Benn, Caroline L / Bond, Brian C / Edelmann, Winfried / Greene, Jonathan R / Bates, Gillian P

Brain : a journal of neurology

2024 Volume 147, Issue 5, Page(s) 1784–1798

Abstract: The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions of hundreds of CAGs have been detected in Huntington's ...

Abstract	The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions of hundreds of CAGs have been detected in Huntington's disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington's disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington's disease brains is required for pathogenesis. Therefore, the pathogenic repeat threshold in brain is longer than (CAG)40, as measured in blood, and is currently unknown. The mismatch repair gene MSH3 has become a major focus for therapeutic development, as unlike other mismatch repair genes, nullizygosity for MSH3 does not cause malignancies associated with mismatch repair deficiency. Potential treatments targeting MSH3 currently under development include gene therapy, biologics and small molecules, which will be assessed for efficacy in mouse models of Huntington's disease. The zQ175 knock-in model carries a mutation of approximately (CAG)185 and develops early molecular and pathological phenotypes that have been extensively characterized. Therefore, we crossed the mutant huntingtin allele onto heterozygous and homozygous Msh3 knockout backgrounds to determine the maximum benefit of targeting Msh3 in this model. Ablation of Msh3 prevented somatic expansion throughout the brain and periphery, and reduction of Msh3 by 50% decreased the rate of expansion. This had no effect on the deposition of huntingtin aggregation in the nuclei of striatal neurons, nor on the dysregulated striatal transcriptional profile. This contrasts with ablating Msh3 in knock-in models with shorter CAG repeat expansions. Therefore, further expansion of a (CAG)185 repeat in striatal neurons does not accelerate the onset of molecular and neuropathological phenotypes. It is striking that highly expanded CAG repeats of a similar size in humans cause disease onset before 2 years of age, indicating that somatic CAG repeat expansion in the brain is not required for pathogenesis. Given that the trajectory for somatic CAG expansion in the brains of Huntington's disease mutation carriers is unknown, our study underlines the importance of administering treatments targeting somatic instability as early as possible.
MeSH term(s)	Huntington Disease/genetics ; Huntington Disease/therapy ; Animals ; Humans ; Trinucleotide Repeat Expansion/genetics ; Mice ; Huntingtin Protein/genetics ; MutS Homolog 3 Protein/genetics ; Disease Models, Animal ; Nerve Tissue Proteins/genetics ; Brain/pathology ; Brain/metabolism
Chemical Substances	Huntingtin Protein ; MutS Homolog 3 Protein ; Nerve Tissue Proteins ; MSH3 protein, human
Language	English
Publishing date	2024-02-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awae063
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Article ; Online: Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model.

Marchionini, Deanna M / Liu, Jeh-Ping / Ambesi-Impiombato, Alberto / Kerker, Kimberly / Cirillo, Kim / Bansal, Mukesh / Mushlin, Rich / Brunner, Daniela / Ramboz, Sylvie / Kwan, Mei / Kuhlbrodt, Kirsten / Tillack, Karsten / Peters, Finn / Rauhala, Leena / Obenauer, John / Greene, Jonathan R / Hartl, Christopher / Khetarpal, Vinod / Lager, Brenda /

Rosinski, Jim / Aaronson, Jeff / Alam, Morshed / Signer, Ethan / Muñoz-Sanjuán, Ignacio / Howland, David / Zeitlin, Scott O

JCI insight

2022 Volume 7, Issue 20

Abstract: We have developed an inducible Huntington's disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term ... ...

Abstract	We have developed an inducible Huntington's disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow-up revealed that the benefits, in all mHtt-lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12 months of age, and late mHtt lowering did not ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefits in humans.
MeSH term(s)	Mice ; Humans ; Animals ; Infant ; Huntington Disease/drug therapy ; Huntington Disease/genetics ; Protein Aggregates ; Huntingtin Protein/genetics ; Huntingtin Protein/cerebrospinal fluid ; Disease Models, Animal ; Corpus Striatum/metabolism ; Disease Progression
Chemical Substances	Protein Aggregates ; Huntingtin Protein
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.161769
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Article ; Online: HCV genotyping using statistical classification approach.

Qiu, Ping / Cai, Xiao-Yan / Ding, Wei / Zhang, Qing / Norris, Ellie D / Greene, Jonathan R

Journal of biomedical science

2009 Volume 16, Page(s) 62

Abstract: The genotype of Hepatitis C Virus (HCV) strains is an important determinant of the severity and aggressiveness of liver infection as well as patient response to antiviral therapy. Fast and accurate determination of viral genotype could provide direction ... ...

Abstract	The genotype of Hepatitis C Virus (HCV) strains is an important determinant of the severity and aggressiveness of liver infection as well as patient response to antiviral therapy. Fast and accurate determination of viral genotype could provide direction in the clinical management of patients with chronic HCV infections. Using publicly available HCV nucleotide sequences, we built a global Position Weight Matrix (PWM) for the HCV genome. Based on the PWM, a set of genotype specific nucleotide sequence "signatures" were selected from the 5' NCR, CORE, E1, and NS5B regions of the HCV genome. We evaluated the predictive power of these signatures for predicting the most common HCV genotypes and subtypes. We observed that nucleotide sequence signatures selected from NS5B and E1 regions generally demonstrated stronger discriminant power in differentiating major HCV genotypes and subtypes than that from 5' NCR and CORE regions. Two discriminant methods were used to build predictive models. Through 10 fold cross validation, over 99% prediction accuracy was achieved using both support vector machine (SVM) and random forest based classification methods in a dataset of 1134 sequences for NS5B and 947 sequences for E1. Prediction accuracy for each genotype is also reported.
MeSH term(s)	Algorithms ; Antiviral Agents/pharmacology ; Base Sequence ; Computational Biology/methods ; DNA Primers/chemistry ; DNA, Viral ; Genes, Viral ; Genotype ; Hepacivirus/genetics ; Models, Genetic ; Molecular Sequence Data ; RNA, Viral/genetics ; Reproducibility of Results ; Sequence Alignment ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; DNA Primers ; DNA, Viral ; RNA, Viral ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48)
Language	English
Publishing date	2009-07-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/1423-0127-16-62
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Article ; Online: Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder.

Leday, Gwenaël G R / Vértes, Petra E / Richardson, Sylvia / Greene, Jonathan R / Regan, Tim / Khan, Shahid / Henderson, Robbie / Freeman, Tom C / Pariante, Carmine M / Harrison, Neil A / Perry, V Hugh / Drevets, Wayne C / Wittenberg, Gayle M / Bullmore, Edward T

Biological psychiatry

2017 Volume 83, Issue 1, Page(s) 70–80

Abstract: Background: Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.: Methods: We used microarray data on whole blood from two independent case- ... ...

Abstract	Background: Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Methods: We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen-Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. Results: A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies). Conclusions: MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.
MeSH term(s)	Biomarkers/blood ; Case-Control Studies ; Depressive Disorder, Major/blood ; Depressive Disorder, Major/genetics ; Depressive Disorder, Major/immunology ; Gene Expression ; Gene Expression Regulation ; Humans ; Immunity, Innate/genetics ; Microarray Analysis ; Transcriptome ; Wernicke Encephalopathy
Chemical Substances	Biomarkers
Language	English
Publishing date	2017-07-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2017.01.021
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Article ; Online: HCV genotyping using statistical classification approach

Norris Ellie D / Zhang Qing / Ding Wei / Cai Xiao-Yan / Qiu Ping / Greene Jonathan R

Journal of Biomedical Science, Vol 16, Iss 1, p

2009 Volume 62

Abstract: Abstract The genotype of Hepatitis C Virus (HCV) strains is an important determinant of the severity and aggressiveness of liver infection as well as patient response to antiviral therapy. Fast and accurate determination of viral genotype could provide ... ...

Abstract	Abstract The genotype of Hepatitis C Virus (HCV) strains is an important determinant of the severity and aggressiveness of liver infection as well as patient response to antiviral therapy. Fast and accurate determination of viral genotype could provide direction in the clinical management of patients with chronic HCV infections. Using publicly available HCV nucleotide sequences, we built a global Position Weight Matrix (PWM) for the HCV genome. Based on the PWM, a set of genotype specific nucleotide sequence "signatures" were selected from the 5' NCR, CORE, E1, and NS5B regions of the HCV genome. We evaluated the predictive power of these signatures for predicting the most common HCV genotypes and subtypes. We observed that nucleotide sequence signatures selected from NS5B and E1 regions generally demonstrated stronger discriminant power in differentiating major HCV genotypes and subtypes than that from 5' NCR and CORE regions. Two discriminant methods were used to build predictive models. Through 10 fold cross validation, over 99% prediction accuracy was achieved using both support vector machine (SVM) and random forest based classification methods in a dataset of 1134 sequences for NS5B and 947 sequences for E1. Prediction accuracy for each genotype is also reported.
Keywords	Medicine ; R
Subject code	006
Language	English
Publishing date	2009-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.

Sehgal, Kartik / Portell, Andrew / Ivanova, Elena V / Lizotte, Patrick H / Mahadevan, Navin R / Greene, Jonathan R / Vajdi, Amir / Gurjao, Carino / Teceno, Tyler / Taus, Luke J / Thai, Tran C / Kitajima, Shunsuke / Liu, Derek / Tani, Tetsuo / Noureddine, Moataz / Lau, Christie J / Kirschmeier, Paul T / Liu, David / Giannakis, Marios /

Jenkins, Russell W / Gokhale, Prafulla C / Goldoni, Silvia / Pinzon-Ortiz, Maria / Hastings, William D / Hammerman, Peter S / Miret, Juan J / Paweletz, Cloud P / Barbie, David A

The Journal of clinical investigation

2020 Volume 131, Issue 2

Abstract: Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, ... ...

Abstract	Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
MeSH term(s)	Animals ; Cell Line, Tumor ; Immunotherapy ; Mice ; Neoplasm Proteins/genetics ; Neoplasm Proteins/immunology ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/therapy ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/immunology ; RNA-Seq ; Single-Cell Analysis ; Spheroids, Cellular/immunology ; Spheroids, Cellular/pathology
Chemical Substances	Neoplasm Proteins ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2020-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI135038
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Article ; Online: Genome wide in silico SNP-tumor association analysis

Simon Jason S / Ding Wei / Kostich Mitch / Wang Luquan / Qiu Ping / Greene Jonathan R

BMC Cancer, Vol 4, Iss 1, p

2004 Volume 4

Abstract: Abstract Background Carcinogenesis occurs, at least in part, due to the accumulation of mutations in critical genes that control the mechanisms of cell proliferation, differentiation and death. Publicly accessible databases contain millions of expressed ... ...

Abstract	Abstract Background Carcinogenesis occurs, at least in part, due to the accumulation of mutations in critical genes that control the mechanisms of cell proliferation, differentiation and death. Publicly accessible databases contain millions of expressed sequence tag (EST) and single nucleotide polymorphism (SNP) records, which have the potential to assist in the identification of SNPs overrepresented in tumor tissue. Methods An in silico SNP-tumor association study was performed utilizing tissue library and SNP information available in NCBI's dbEST (release 092002) and dbSNP (build 106). Results A total of 4865 SNPs were identified which were present at higher allele frequencies in tumor compared to normal tissues. A subset of 327 (6.7%) SNPs induce amino acid changes to the protein coding sequences. This approach identified several SNPs which have been previously associated with carcinogenesis, as well as a number of SNPs that now warrant further investigation Conclusions This novel in silico approach can assist in prioritization of genes and SNPs in the effort to elucidate the genetic mechanisms underlying the development of cancer.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2004-01-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Analysis of a human brain transcriptome map

Greene Jonathan R / Liu Suxing / Benbow Lawrence / Qiu Ping / Wang Luquan

BMC Genomics, Vol 3, Iss 1, p

2002 Volume 10

Abstract: Abstract Background Genome wide transcriptome maps can provide tools to identify candidate genes that are over-expressed or silenced in certain disease tissue and increase our understanding of the structure and organization of the genome. Expressed ... ...

Abstract	Abstract Background Genome wide transcriptome maps can provide tools to identify candidate genes that are over-expressed or silenced in certain disease tissue and increase our understanding of the structure and organization of the genome. Expressed Sequence Tags (ESTs) from the public dbEST and proprietary Incyte LifeSeq databases were used to derive a transcript map in conjunction with the working draft assembly of the human genome sequence. Results Examination of ESTs derived from brain tissues (excluding brain tumor tissues) suggests that these genes are distributed on chromosomes in a non-random fashion. Some regions on the genome are dense with brain-enriched genes while some regions lack brain-enriched genes, suggesting a significant correlation between distribution of genes along the chromosome and tissue type. ESTs from brain tumor tissues have also been mapped to the human genome working draft. We reveal that some regions enriched in brain genes show a significant decrease in gene expression in brain tumors, and, conversely that some regions lacking in brain genes show an increased level of gene expression in brain tumors. Conclusions This report demonstrates a novel approach for tissue specific transcriptome mapping using EST-based quantitative assessment.
Keywords	Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Genetics ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Subject code	616
Language	English
Publishing date	2002-04-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Hepatitis C virus whole genome position weight matrix and robust primer design

Greene Jonathan R / Wang Luquan / Cai Xiao-Yan / Qiu Ping / Malcolm Bruce

BMC Microbiology, Vol 2, Iss 1, p

2002 Volume 29

Abstract: Abstract Background The high degree of sequence heterogeneity found in Hepatitis C virus (HCV) isolates, makes robust nucleic acid-based assays difficult to generate. Polymerase chain reaction based techniques, require efficient and specific sequence ... ...

Abstract	Abstract Background The high degree of sequence heterogeneity found in Hepatitis C virus (HCV) isolates, makes robust nucleic acid-based assays difficult to generate. Polymerase chain reaction based techniques, require efficient and specific sequence recognition. Generation of robust primers capable of recognizing a wide range of isolates is a difficult task. Results A position weight matrix (PWM) and a consensus sequence were built for each region of HCV and subsequently assembled into a whole genome consensus sequence and PWM. For each of the 10 regions, the number of occurrences of each base at a given position was compiled. These counts were converted to frequencies that were used to calculate log odds scores. Using over 100 complete and 14,000 partial HCV genomes from GenBank, a consensus HCV genome sequence was generated along with a PWM reflecting heterogeneity at each position. The PWM was used to identify the most conserved regions for primer design. Conclusions This approach allows rapid identification of conserved regions for robust primer design and is broadly applicable to sets of genomes with all levels of genetic heterogeneity.
Keywords	Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Subject code	670
Language	English
Publishing date	2002-09-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article: Computational analysis of composite regulatory elements

Qiu, Ping / Ding, Wei / Jiang, Ying / Greene, Jonathan R / Wang, Luquan

Mammalian genome. 2002 June, v. 13, no. 6

2002

Abstract: Combinatorial regulation is a powerful mechanism for generating specificity in gene expression, and it is thought to play a pivotal role in the formation of the complex gene regulatory networks found in higher eukaryotes. The term ``Composite Element'' ( ... ...

Abstract	Combinatorial regulation is a powerful mechanism for generating specificity in gene expression, and it is thought to play a pivotal role in the formation of the complex gene regulatory networks found in higher eukaryotes. The term ``Composite Element'' (CE) refers to a minimal functional unit where protein–DNA and protein–protein interactions contribute to a highly specific pattern of gene transcriptional regulation. Identification of composite elements will help to better understand gene regulation networks. Experimentally identified CEs are limited in number, and the currently available CE database COMPEL is based on such published information. Here, based on the statistical analysis of over-represented adjacent transcription factor binding sites, we describe a computational method to predict composite regulatory elements in genomic sequences. The algorithm proved to be efficient for extracting composite elements that had been experimentally confirmed and documented in the COMPEL database. Furthermore, putative new composite elements are predicted based on this method, and we have been able to confirm some of our predictions which are not included in the COMPEL database by searching published information.
Keywords	algorithms ; binding sites ; databases ; eukaryotic cells ; gene expression ; nucleotide sequences ; prediction ; regulator genes ; statistical analysis ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2002-06
Size	p. 327-332.
Publishing place	Springer-Verlag
Document type	Article
ZDB-ID	1058547-3
ISSN	1432-1777 ; 0938-8990
ISSN (online)	1432-1777
ISSN	0938-8990
DOI	10.1007/s00335-001-2141-8
Database	NAL-Catalogue (AGRICOLA)

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