Loss of β-Actin Leads to Accelerated Mineralization and Dysregulation of Osteoblast-Differentiation Genes during Osteogenic Reprogramming.
Loss of β-Actin Leads to Accelerated Mineralization and Dysregulation of Osteoblast-Differentiation Genes during Osteogenic Reprogramming.
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β-肌动蛋白的丧失会导致成骨重编程过程中成骨细胞分化基因的加速矿化和失调。
DOI：
10.1002/advs.202002261
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Percipalle P
中科院分区：
文献类型：
--
作者：
Gjorgjieva T;Xie X;Commins P;Pasricha R;Mahmood SR;Gunsalus KC;Naumov P;Percipalle P
肌动蛋白在细胞质和细胞核中都起着重要的作用。在细胞核中，β -肌动蛋白通过巩固神经元基因程序转录所需的异染色质景观来调节神经元重编程，但它是否在其他分化模式中发挥作用尚不清楚。为了探索β -肌动蛋白在成骨过程中的潜在作用，在体外使用小分子将β -肌动蛋白野生型（WT）和β -肌动蛋白敲除型（KO）小鼠胚胎成纤维细胞（mef）重编程为成骨细胞样细胞。研究发现，β -肌动蛋白的缺失导致矿化表型加速（超矿化），并伴有细胞外羟基磷灰石微晶的形成增强，这些微晶以微颗粒的形式起源于线粒体。这种表型是线粒体基因快速上调的结果，包括在重编程的KO细胞中参与氧化磷酸化（OXPHOS）的基因。研究进一步发现，成骨基因程序在WT和KO细胞之间受到不同的调控，基因簇表现出不同的时间表达模式。β -肌动蛋白在成骨重编程中的新功能是通过线粒体机制控制细胞介导的矿化。目前的研究强调了β -肌动蛋白在成骨分化过程中转录重编程的新功能，导致细胞介导的矿化。β -肌动蛋白通过在成骨过程中调节成骨因子和线粒体基因的表达来完成这项任务。这些观察结果支持细胞骨架蛋白如肌动蛋白在发育和分化过程中参与基因表达调控的新观点。
Actin plays fundamental roles in both the cytoplasm and the cell nucleus. In the nucleus, β‐actin regulates neuronal reprogramming by consolidating a heterochromatin landscape required for transcription of neuronal gene programs, yet it remains unknown whether it has a role in other differentiation models. To explore the potential roles of β‐actin in osteogenesis, β‐actin wild‐type (WT) and β‐actin knockout (KO) mouse embryonic fibroblasts (MEFs) are reprogrammed to osteoblast‐like cells using small molecules in vitro. It is discovered that loss of β‐actin leads to an accelerated mineralization phenotype (hypermineralization), accompanied with enhanced formation of extracellular hydroxyapatite microcrystals, which originate in the mitochondria in the form of microgranules. This phenotype is a consequence of rapid upregulation of mitochondrial genes including those involved in oxidative phosphorylation (OXPHOS) in reprogrammed KO cells. It is further found that osteogenic gene programs are differentially regulated between WT and KO cells, with clusters of genes exhibiting different temporal expression patterns. A novel function for β‐actin in osteogenic reprogramming through a mitochondria‐based mechanism that controls cell‐mediated mineralization is proposed. The present study highlights a new function for β‐actin in transcriptional reprograming during osteogenic differentiation, leading to cell‐mediated mineralization. β‐actin performs this task by regulating expression of osteogenic factors and mitochondrial genes during osteogenesis. These observations support the novel involvement of cytoskeletal proteins such as actin in gene expression regulation during development and differentiation.
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DOI：
10.1073/pnas.1208916109
发表时间：
2012-08-28
影响因子：
11.1
作者：
Boonrungsiman, Suwimon;Gentleman, Eileen;Stevens, Molly M.
通讯作者：
Stevens, Molly M.
影响因子：
4.3
作者：
Carafoli, Ernesto
通讯作者：
Carafoli, Ernesto
影响因子：
2.7
作者：
RICKARD, DJ;SULLIVAN, TA;KAZHDAN, I
通讯作者：
KAZHDAN, I
DOI：
10.1007/978-1-4419-1050-9_5
发表时间：
2010-01-01
期刊：
OSTEOIMMUNOLOGY: INTERACTIONS OF THE IMMUNE AND SKELETAL SYSTEMS II
影响因子：
--
作者：
Komori, Toshihisa
通讯作者：
Komori, Toshihisa
影响因子：
2.1
作者：
Schroeder, Tania M.;Jensen, Eric D.;Westendorf, Jennifer J.
通讯作者：
Westendorf, Jennifer J.