HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles.
HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles.
复制标题
DOI：
10.1101/gad.234468.113
复制
发表时间：
2014-04-15
影响因子：
10.5
通讯作者：
Puri PL
中科院分区：
文献类型：
--
作者：
Saccone V;Consalvi S;Giordani L;Mozzetta C;Barozzi I;Sandoná M;Ryan T;Rojas-Muñoz A;Madaro L;Fasanaro P;Borsellino G;De Bardi M;Frigè G;Termanini A;Sun X;Rossant J;Bruneau BG;Mercola M;Minucci S;Puri PL
成纤维脂肪祖细胞（FAP）是骨骼肌再生环境的组成部分，强烈影响肌营养不良症的发病机制。Saccone等人显示HDAC、肌肉特异性微RNA（myomiR）和SWI/SNF染色质重塑复合物组分BAF 60变体一起起作用以调节mdx小鼠的营养不良肌肉中FAP的命运。这些结果揭示了早期和晚期mdx小鼠肌肉再生能力的差异，并为促进营养不良肌肉的治疗性再生提供了分子基础。成纤维脂肪祖细胞（FAP）是骨骼肌再生环境的重要组成部分。FAP是否支持肌肉再生或促进纤维脂肪形成变性正在成为肌肉疾病（包括杜氏肌营养不良症（DMD））发病机制的关键决定因素。然而，控制FAP谱系定型和活性的分子机制目前尚不清楚。我们在这里表明，HDAC-myomiR-BAF 60变异网络调节mdx小鼠营养不良肌肉中FAP的命运。基因表达微阵列的组合分析、通过核酸酶可及性（NA）进行的全基因组染色质重塑，结合下一代测序（NA-seq）、小RNA测序（RNA-seq）和针对SWI/SNF BAF 60变体的microRNA（miR）高通量筛选（HTS）揭示了HDAC抑制剂（HDACis）在疾病早期阶段抑制来自营养不良肌肉的FAP中的“潜在”肌原性程序。具体而言，HDAC抑制诱导肌源性转录机制的两个核心组分MYOD和BAF 60 C，并上调靶向替代BAF 60变体BAF 60 A和BAF 60 B的肌源性miR（myomiR）（miR-1.2、miR-133和miR-206），最终指导促肌源性分化，同时抑制纤维-脂肪形成表型。相比之下，来自晚期营养不良肌肉的FAP对HDACi诱导的肌原基因座染色质重塑具有抵抗力，并且无法激活促肌原表型。这些结果揭示了一个以前不受重视的疾病阶段特异性双能性间充质细胞内营养不良的肌肉再生环境。通过HDACis的表观遗传干预解决这种双能性为靶细胞的原位重编程以促进营养不良肌肉的治疗性再生提供了分子理论基础。
Fibro-adipogenic progenitors (FAPs) are components of the skeletal muscle regenerative environment that strongly influence the pathogenesis of muscular dystrophies. Saccone et al. show that HDAC, muscle-specific microRNAs (myomiRs), and SWI/SNF chromatin remodeling complex component BAF60 variants function together to regulate the fate of FAPs in dystrophic muscles of mdx mice. The results shed light on differences between the muscle-regenerative capacities of early and late stage mdx mice and provide a molecular rationale to promote the therapeutic regeneration of dystrophic muscles. Fibro-adipogenic progenitors (FAPs) are important components of the skeletal muscle regenerative environment. Whether FAPs support muscle regeneration or promote fibro-adipogenic degeneration is emerging as a key determinant in the pathogenesis of muscular diseases, including Duchenne muscular dystrophy (DMD). However, the molecular mechanism that controls FAP lineage commitment and activity is currently unknown. We show here that an HDAC–myomiR–BAF60 variant network regulates the fate of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray, genome-wide chromatin remodeling by nuclease accessibility (NA) combined with next-generation sequencing (NA-seq), small RNA sequencing (RNA-seq), and microRNA (miR) high-throughput screening (HTS) against SWI/SNF BAF60 variants revealed that HDAC inhibitors (HDACis) derepress a “latent” myogenic program in FAPs from dystrophic muscles at early stages of disease. Specifically, HDAC inhibition induces two core components of the myogenic transcriptional machinery, MYOD and BAF60C, and up-regulates the myogenic miRs (myomiRs) (miR-1.2, miR-133, and miR-206), which target the alternative BAF60 variants BAF60A and BAF60B, ultimately directing promyogenic differentiation while suppressing the fibro-adipogenic phenotype. In contrast, FAPs from late stage dystrophic muscles are resistant to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the promyogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bipotency by epigenetic intervention with HDACis provides a molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles.
登录
查看更多内容
DOI：
10.1083/jcb.200603008
发表时间：
2006-08-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim HK;Lee YS;Sivaprasad U;Malhotra A;Dutta A
通讯作者：
Dutta A
DOI：
10.1146/annurev-cellbio-051809-102012
发表时间：
2010
影响因子：
11.3
作者：
Lessard JA;Crabtree GR
通讯作者：
Crabtree GR
影响因子：
64.5
作者：
Heredia JE;Mukundan L;Chen FM;Mueller AA;Deo RC;Locksley RM;Rando TA;Chawla A
通讯作者：
Chawla A
DOI：
10.1073/pnas.0805514105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Colussi, Claudia;Mozzetta, Chiara;Gaetano, Carlo
通讯作者：
Gaetano, Carlo
影响因子：
5.7
作者：
Consalvi, Silvia;Mozzetta, Chiara;Saccone, Valentina
通讯作者：
Saccone, Valentina