在GDF5的复杂调节相互作用塑造了关节形态和骨关节炎疾病风险
Clarissa R Coveney1,2, David Maridas3, Hao Chen4
1Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
bioRxiv : the preprint server for biology
|November 18, 2024
概括
与疾病相关的遗传变异,如GDF5基因中的变异,需要了解复杂的调节相互作用. 表观和局部表观基因组背景显著影响疾病风险,而不仅仅是个体变异.
科学领域:
- 遗传学 遗传学 是一个
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 骨生物学 骨生物学
背景情况:
- 全基因组关联研究 (GWAS) 识别了与疾病相关的基因位置,但确定因果变异需要了解它们的监管背景.
- GDF5位点在骨生物学中得到了很好的研究,与许多疾病有关,具有复杂的cis-regulatory架构.
研究的目的:
- 为了研究GDF5位点的调节相互作用.
- 在GDF5.5中建模疾病相关变异的体外和体内效应.
- 了解表观遗传学和表观遗传学因素在GDF5介导疾病风险中的作用.
主要方法:
- 质疑GDF5调控区域及其对基因表达的影响.
- 在小鼠GDF5疾病风险变异的体外和体外建模.
- 分析表观遗传激活/抑制模式及其与关节特异性表达和疾病风险的相关性.
- 评估GDF5变体之间的表皮性相互作用.
主要成果:
- 在GDF5调节区域的局部表观遗传状态影响关节特异性表达和疾病风险.
- 一种备受引用的GDF5风险变体在小鼠模型中没有直接影响表达,关节形态或疾病.
- 在模拟风险变体和监管区域的其他变体之间确定了显著的表皮表达相互作用.
结论:
- 表观性相互作用和局部表观性是GDF5相关疾病病因的关键因素.
- 高GWAS意义的个别变异不应仅仅被认为是因果关系,而不考虑它们的监管和表观背景.
- 了解动态表观遗传学和表观遗传学景观对于准确解释GWAS发现至关重要.
相关概念视频
01:24Bone Formation by Endochondral Ossification
3.9K
Bone formation, or ossification, begins around the sixth to seventh week of embryonic development. Most bones develop from a cartilaginous template through the process of endochondral ossification. Cartilage formation begins when clusters of mesenchymal cells differentiate into chondrocytes. These chondrocytes proliferate rapidly and secrete an extracellular matrix that becomes encased in a membrane called the perichondrium. The resulting cartilage model provides a template that resembles the...
3.9K
01:20The JAK-STAT Signaling Pathway
8.7K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
8.7K
01:16TGF - β Signaling Pathway
7.2K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.2K
01:31Osteoclasts in Bone Remodeling
2.8K
Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during...
2.8K
01:23Regulation of Expression at Multiple Steps
873
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
873
01:11Genome-wide Association Studies-GWAS
12.5K
Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
GWAS does not require the identification of the target gene involved in...
12.5K