54 research outputs found
GRIP1 enhances estrogen receptor Ī±-dependent extracellular matrix gene expression in chondrogenic cells
SummaryObjectiveThe role of postmenopause on the pathogenesis of cartilage degeneration has been an open question. We assessed cartilage degeneration in estrogen receptor (ER)Ī± null mice and examined the role of glucocorticoid receptor-interacting protein 1 (GRIP1) in the ERĪ±-dependent transcription of a type II collagen gene (col2a1) with special reference to a crosstalk with the transforming growth factor (TGF)-Ī² signaling pathway.MethodsThe vertebral cartilaginous endplate from female ERĪ± null mice was subjected to histological analyses. Col2a1 expression of primary chondrocytes (PCs) obtained from ERĪ± null mice after 17Ī²-estradiol (E2) and TGF-Ī²1 stimulation was examined by reverse transcription polymerase chain reaction (RT-PCR). Estrogen response element (ERE) or col2a1 promoterāenhancer luciferase reporter system was used to investigate the crosstalk among ERĪ±, GRIP1, and MKK6. Col2a1 expression and glycosaminoglycan (GAG) content were measured in ATDC5 cells treated with GRIP1 small interfering RNA (siRNA).ResultsERĪ± deficiency clearly accelerated impairment of the vertebral cartilaginous endplate. E2 and TGF-Ī²1 stimulation increased col2a1 expression in PC from wild-type mice, but not that from ERĪ± null mice. The same stimulation increased the col2a1 promoterāenhancer reporter activity, and the elevated activity was decreased by dominant-negative ERĪ± and p38 mitogen-activated protein kinase (MAPK) inhibitor. GRIP1 increased the E2-dependent ERE activation in the presence of ERĪ± and constitutive-active MKK6. GRIP1 siRNA repressed col2a1 expression and GAG production in ATDC5 cells.ConclusionsCrosstalks between ERĪ±/GRIP1 and TGF-Ī²/MKK6/p38 MAPK pathway have protective roles on cartilage metabolism via regulating the extracellular matrices expression. The finding may lead to the development of a novel therapeutic approach for cartilage degeneration
Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study
IntroductionAdolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated.Material and methodsMendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese.ResultsSignificant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 Ć 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 Ć 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 Ć 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI.ConclusionsOur Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS
Variant PRC1 Complex-Dependent H2A Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation
Chromatin modifying activities inherent to polycomb
repressive complexes PRC1 and PRC2 play an
essential role in gene regulation, cellular differentiation, and development. However, the mechanisms
by which these complexes recognize their target
sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to
occur through a hierarchical process, dependent
on prior nucleation of PRC2 and placement of
H3K27me3. Here, using a de novo targeting assay
in mouse embryonic stem cells we unexpectedly
discover that PRC1-dependent H2AK119ub1 leads
to recruitment of PRC2 and H3K27me3 to effectively
initiate a polycomb domain. This activity is restricted
to variant PRC1 complexes, and genetic ablation
experiments reveal that targeting of the variant
PCGF1/PRC1 complex by KDM2B to CpG islands is
required for normal polycomb domain formation
and mouse development. These observations provide a surprising PRC1-dependent logic for PRC2
occupancy at target sites in vivo.This study was funded by the Wellcome Trust (WT0834922 and WT081385), CRUK (C28585/A10839), NIHR, EMBO, Lister Institute of Preventative Medicine, RIKEN, MEXT, and JST CRES
Application of CR-39 plastic nuclear track detectors for quality assurance of mixed oxide fuel pellets
A CR-39 plastic nuclear track detector was used for quality assurance of mixed oxide fuel pellets for next-generation nuclear power plants. Plutonium (Pu) spot sizes and concentrations in the pellets are significant parameters for safe use in the plants. We developed an automatic Pu detection system based on dense Ī±-radiation tracks in the CR-39 detectors. This system would greatly improve image processing time and measurement accuracy, and will be a powerful tool for rapid pellet quality assurance screening
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