Abstract:
:Emerging evidence implicates epigenetic mechanisms in the pathogenesis of rheumatoid arthritis (RA). In this study, we have investigated the role of histone deacetylase (HDAC) enzymes in RA synovial fibroblasts (RASFs), a key cellular mediator of cartilage and bone destruction and determined effects of HDAC1 inhibition on both RASF phenotype in vitro, and joint inflammation and damage in the collagen-induced arthritis (CIA) model. Expression of HDACs 1-11 messenger ribonucleic acid (mRNA) was compared between RASFs and osteoarthritic synovial fibroblast (OASFs) using quantitative polymerase chain reaction. HDAC1 expression in RASFs was inhibited using small interfering RNA (siRNA) technology to assess effects on invasiveness, migration, proliferation and apoptosis. Effects of HDAC1 knockdown (KD) on the transcriptome were assessed using gene microarrays. The effects of siRNA-mediated HDAC(KD) on clinical scores, tissue inflammation and damage were assessed on CIA up to 47 days following immunization. Expression of HDAC1 was significantly higher in RASFs than OASFs. HDAC1(KD) resulted in reduced proliferation, invasion and migration in vitro and transcriptome profiling revealed effects on expression of genes regulating proliferation migration and inflammation. Furthermore, inhibition of HDAC1 in CIA resulted in reduced joint swelling, cartilage and bone damage and lower tumor necrosis factor in joint tissue. These results implicate HDAC1 as an important mediator of tissue damage in RA and support the potential therapeutic utility of inhibitors of this enzyme.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Hawtree S,Muthana M,Wilkinson JM,Akil M,Wilson AGdoi
10.1093/hmg/ddv258subject
Has Abstractpub_date
2015-10-01 00:00:00pages
5367-77issue
19eissn
0964-6906issn
1460-2083pii
ddv258journal_volume
24pub_type
杂志文章abstract::Autosomal Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humero-peroneal muscle wasting and weakness, early joint contractures and dilated ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz056
更新日期:2019-07-01 00:00:00
abstract::Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt mu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds514
更新日期:2013-04-15 00:00:00
abstract::Genome-wide association studies and, more recently, next-generation sequencing studies have accelerated the investigation of complex human traits by providing a wealth of association data linking genetic variants to diseases and other phenotypic traits. These data promise to transform our understanding of the molecula...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/dds363
更新日期:2012-10-15 00:00:00
abstract::Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy275
更新日期:2018-11-15 00:00:00
abstract::We have previously developed a functional assay in yeast for the copper transporter, ATP7B, defective in Wilson disease (WND). Analysis of WND variant ATP7B proteins revealed that several were able to completely, or nearly completely, complement a mutant yeast strain in which the ATP7B ortholog CCC2 was disrupted, ind...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.13.1927
更新日期:2000-08-12 00:00:00
abstract::The brain-specific miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 domain is implicated in several aspects of brain development and function, particularly in fine-tuning the dendritic outgrowth and spine remodelling of hippocampal neurons. Whether it might influence behaviour and memory-related processes has n...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv510
更新日期:2016-02-15 00:00:00
abstract::Congenital nephrotic syndrome of the Finnish type (CNF or NPHS1) is an autosomal recessive kidney disorder resulting in severe proteinurea and renal dysfunction. Although the disease occurs predominantly in the Finnish population, many cases in other populations have also been reported. The disease gene (NPHS1) encode...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.23.2637
更新日期:2001-11-01 00:00:00
abstract::Transposable elements (TEs) are major sources of new exons in higher eukaryotes. Almost half of the human genome is derived from TEs, and many types of TEs have the potential to exonize. In this work, we conducted a large-scale analysis of human exons derived from mammalian-wide interspersed repeats (MIRs), a class of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp152
更新日期:2009-06-15 00:00:00
abstract::Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by mutations in the G6PC gene, encoding the catalytic subunit of glucose-6-phosphatase. Early symptoms include severe fasting intolerance, failure to thrive and hepatomegaly, biochemically associated with nonketotic hypoglycemia, fasting...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz283
更新日期:2020-01-15 00:00:00
abstract::Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv402
更新日期:2015-12-15 00:00:00
abstract::NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and li...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg321
更新日期:2003-11-15 00:00:00
abstract::Multiple studies have underscored the importance of loss of tumor suppressor genes in the development of human cancer. To identify these genes, we used somatic cell hybrids in a functional assay for tumor suppression in vivo. A tumor suppressor gene in 11p15.5 was detected by transferring single human chromosomes into...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.2.239
更新日期:1996-02-01 00:00:00
abstract::Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn106
更新日期:2008-07-15 00:00:00
abstract::In order to identify genes in the Prader-Willi/Angelman syndrome critical region, radiolabeled cDNA probes from poly(A)+ RNA from mouse tissues were used to identify potential exon-containing genomic DNA fragments in cosmid or phage clones from appropriate yeast artificial chromosomes, and these fragments were subsequ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.2.309
更新日期:1994-02-01 00:00:00
abstract::Expansion of a polyglutamine tract in ataxin-3 (AT3) results in spinocerebellar ataxia type 3/Machado-Joseph disease, one of the nine polyglutamine neurodegenerative diseases. Understanding the normal functions of AT3 as well as its function in the context of expansion of the polyglutamine tract is critical for unders...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl164
更新日期:2006-08-15 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are the two common neurodegenerative diseases that have been associated with the GGGGCC·GGCCCC repeat RNA expansion in a noncoding region of C9orf72. It has been previously reported that unconventional repeat-associated non-ATG (RAN) translation of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv005
更新日期:2015-05-01 00:00:00
abstract::Coronary heart disease (CHD) is the leading cause of death worldwide. Mitochondrial genetic determinant for the development of CHD remains poorly explored. We report there the clinical, genetic, molecular and biochemical characterization of a four-generation Chinese family with maternally inherited CHD. Thirteen of 32...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt256
更新日期:2013-10-15 00:00:00
abstract::X chromosome inactivation (XCI) is an epigenetic mechanism that silences the majority of genes on one X chromosome in females. Previous studies have suggested that the spread of XCI might be facilitated in part by common repeats such as long interspersed nuclear elements (LINEs). However, owing to the unusual sequence...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt553
更新日期:2014-03-01 00:00:00
abstract::Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and diverg...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz151
更新日期:2019-10-01 00:00:00
abstract::For the past 40 years, research into Parkinson's disease (PD) has been predominantly the province of epidemiologists interested in pursuing the connection between the disease and environmental factors such as viral infection or neurotoxins. Hereditary influences were actually discounted because of a high monozygotic t...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/6.10.1687
更新日期:1997-01-01 00:00:00
abstract::The gene encoding the gamma chain of the lymphocyte interleukin-2 receptor has been cloned and shown to be required to associate with the beta chain in order for IL-2 internalization and cell activation to occur (1). We considered this gene, IL2RG, a candidate for the X-linked form of severe combined immunodeficiency ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.8.1099
更新日期:1993-08-01 00:00:00
abstract::Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw023
更新日期:2016-04-01 00:00:00
abstract::Fragile X syndrome, a common form of inherited mental retardation, is caused by loss of the fragile X mental retardation protein (FMRP). As a selective RNA-binding protein, FMRP is localized predominately in cytoplasm, where it regulates translational control. However, there is a small portion of FMRP present in the n...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu241
更新日期:2014-10-01 00:00:00
abstract::Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy290
更新日期:2018-12-01 00:00:00
abstract::The oculo-auriculo-vertebral spectrum (OAVS) (OMIM % 164210) is a common developmental disorder characterized by hemifacial microsomia, epibulbar tumours, ear malformation and vertebral anomalies. Although rare familial cases suggest that OAVS has a genetic basis, no genetic defect has been identified so far. In a pat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi474
更新日期:2006-02-15 00:00:00
abstract::Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the disease protein, huntingtin. In HD patients and transgenic mice, the affected neurons form characteristic ubiquitin-positive nuclear inclusions (NIs). We have established ecdysone-inducible stable mou...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.13.2009
更新日期:2000-08-12 00:00:00
abstract::Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq471
更新日期:2011-01-15 00:00:00
abstract::Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity a...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds502
更新日期:2013-03-01 00:00:00
abstract::Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives ris...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr614
更新日期:2012-04-15 00:00:00
abstract::Missense mutations (K141N and K141E) in the alpha-crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is curre...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq234
更新日期:2010-08-15 00:00:00