Evolutionary insights into primate skeletal gene regulation using a comparative cell culture model.
Evolutionary insights into primate skeletal gene regulation using a comparative cell culture model.
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DOI：
10.1371/journal.pgen.1010073
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发表时间：
2022-03
期刊：
影响因子：
4.5
通讯作者：
Gilad Y
中科院分区：
文献类型：
--
作者：
Housman G;Briscoe E;Gilad Y
灵长类动物复杂骨骼特征的进化可能同时受到遗传和环境因素的影响。因为使用功能基因组学方法研究骨骼组织是出了名的具有挑战性，即使在人类身上，它们的特征仍然很差，更不用说跨越多个物种了。从骨骼中获取功能基因组数据所涉及的挑战，以及从非人类类人猿中获取此类组织的困难，促使我们考虑使用一种替代的体外系统来比较研究骨骼细胞类型的基因调控。具体地说，我们将6个人(智人)和6个黑猩猩(泛啮齿动物)诱导的多能干细胞系(IPSCs)分化为间充质干细胞(MSCs)，然后再分化为成骨细胞(骨细胞)。我们使用标准方法验证了分化，并收集了来自多个样本的100,000多个细胞的单细胞RNA测序数据，并在分化的每个阶段复制。虽然我们研究的大多数基因在不同物种之间表现出保守的表达模式，但数百个基因在成骨分化阶段内和跨成骨分化阶段在人类和黑猩猩之间存在差异表达(DE)。其中一些种间DE基因显示出与骨骼组织性状发育相关的功能丰富。此外，主题建模表明，随着细胞的成熟，种间基因程序变得更加明显。总体而言，我们建议这个体外模型可以用来识别可能导致物种间骨骼特征差异的种间调控差异。灵长类动物表现出一系列骨骼形态和对骨骼疾病的易感性，但这些表型差异的分子基础尚不清楚。由于与采集样本相关的伦理和实践挑战，灵长类骨骼组织中基因表达变异的研究受到极大的限制。然而，研究灵长类骨骼组织中基因调控的能力对于了解灵长类骨骼是如何进化的至关重要。因此，我们开发了一种比较灵长类骨骼细胞培养模型，允许我们在人类和黑猩猩从干细胞分化为骨细胞的过程中获得一系列细胞类型。虽然大多数基因表达模式在物种之间是保守的，但我们也发现了数百个在分化阶段和跨分化阶段在人类和黑猩猩之间差异表达的基因。我们还根据成骨阶段对细胞进行了分类，并确定了可能导致骨骼特征差异的其他种间差异表达基因。我们预计，该模型将对探索与灵长类骨骼生物学和发育中的基因调控变异相关的问题非常有用。
The evolution of complex skeletal traits in primates was likely influenced by both genetic and environmental factors. Because skeletal tissues are notoriously challenging to study using functional genomic approaches, they remain poorly characterized even in humans, let alone across multiple species. The challenges involved in obtaining functional genomic data from the skeleton, combined with the difficulty of obtaining such tissues from nonhuman apes, motivated us to consider an alternative in vitro system with which to comparatively study gene regulation in skeletal cell types. Specifically, we differentiated six human (Homo sapiens) and six chimpanzee (Pan troglodytes) induced pluripotent stem cell lines (iPSCs) into mesenchymal stem cells (MSCs) and subsequently into osteogenic cells (bone cells). We validated differentiation using standard methods and collected single-cell RNA sequencing data from over 100,000 cells across multiple samples and replicates at each stage of differentiation. While most genes that we examined display conserved patterns of expression across species, hundreds of genes are differentially expressed (DE) between humans and chimpanzees within and across stages of osteogenic differentiation. Some of these interspecific DE genes show functional enrichments relevant in skeletal tissue trait development. Moreover, topic modeling indicates that interspecific gene programs become more pronounced as cells mature. Overall, we propose that this in vitro model can be used to identify interspecific regulatory differences that may have contributed to skeletal trait differences between species. Primates display a range of skeletal morphologies and susceptibilities to skeletal diseases, but the molecular basis of these phenotypic differences is unclear. Studies of gene expression variation in primate skeletal tissues are extremely restricted due to the ethical and practical challenges associated with collecting samples. Nevertheless, the ability to study gene regulation in primate skeletal tissues is crucial for understanding how the primate skeleton has evolved. We therefore developed a comparative primate skeletal cell culture model that allows us to access a spectrum of human and chimpanzee cell types as they differentiate from stem cells into bone cells. While most gene expression patterns are conserved across species, we also identified hundreds of differentially expressed genes between humans and chimpanzees within and across stages of differentiation. We also classified cells by osteogenic stage and identified additional interspecific differentially expressed genes which may contribute to skeletal trait differences. We anticipate that this model will be extremely useful for exploring questions related to gene regulation variation in primate bone biology and development.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
4.6
作者：
Chou, Ching-Heng;Jain, Vaibhav;Kraus, Virginia B.
通讯作者：
Kraus, Virginia B.
影响因子：
4.5
作者：
Dey, Kushal K.;Hsiao, Chiaowen Joyce;Stephens, Matthew
通讯作者：
Stephens, Matthew
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1002/jor.24957
发表时间：
2021-10
期刊：
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
影响因子：
--
作者：
Housman G;Quillen EE;Stone AC
通讯作者：
Stone AC