Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation.
Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation.
复制标题
通过 mTORC1 介导的蛋白质翻译调节红细胞生成过程中的线粒体生物发生。
DOI：
10.1038/ncb3527
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发表时间：
2017-06
影响因子：
21.3
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Liu X;Zhang Y;Ni M;Cao H;Signer RAJ;Li D;Li M;Gu Z;Hu Z;Dickerson KE;Weinberg SE;Chandel NS;DeBerardinis RJ;Zhou F;Shao Z;Xu J
基因组分析的进展提出了解释DNA和RNA的变化如何转化为连接基因型和表型的蛋白质的新挑战。在这里，我们比较了人类初级造血干细胞/祖细胞和红系祖细胞基因组尺度的蛋白质组学和转录组学变化，并揭示了通过转录后调控增强的线粒体生物发生相关途径。线粒体因子包括TFAM和PHB2在红细胞分化过程中通过蛋白翻译被选择性调节。红细胞中TFAM的缺失会改变细胞内代谢，导致组蛋白乙酰化升高，基因表达失调，线粒体和红细胞生成缺陷。从机制上讲，mTORC1信号被增强，通过top样基序促进线粒体相关转录物的翻译。线粒体或mTORC1的遗传和药理学扰动在体外和体内特异性地损害红细胞生成。我们的研究支持了红细胞线粒体转录后控制的机制，并可能与线粒体疾病和衰老相关的血液学缺陷直接相关。
Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary hematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signaling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to hematologic defects associated with mitochondrial diseases and aging.
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影响因子：
64.8
作者：
Kim, Min-Sik;Pinto, Sneha M.;Getnet, Derese;Nirujogi, Raja Sekhar;Manda, Srikanth S.;Chaerkady, Raghothama;Madugundu, Anil K.;Kelkar, Dhanashree S.;Isserlin, Ruth;Jain, Shobhit;Thomas, Joji K.;Muthusamy, Babylakshmi;Leal-Rojas, Pamela;Kumar, Praveen;Sahasrabuddhe, Nandini A.;Balakrishnan, Lavanya;Advani, Jayshree;George, Bijesh;Renuse, Santosh;Selvan, Lakshmi Dhevi N.;Patil, Arun H.;Nanjappa, Vishalakshi;Radhakrishnan, Aneesha;Prasad, Samarjeet;Subbannayya, Tejaswini;Raju, Rajesh;Kumar, Manish;Sreenivasamurthy, Sreelakshmi K.;Marimuthu, Arivusudar;Sathe, Gajanan J.;Chavan, Sandip;Datta, Keshava K.;Subbannayya, Yashwanth;Sahu, Apeksha;Yelamanchi, Soujanya D.;Jayaram, Savita;Rajagopalan, Pavithra;Sharma, Jyoti;Murthy, Krishna R.;Syed, Nazia;Goel, Renu;Khan, Aafaque A.;Ahmad, Sartaj;Dey, Gourav;Mudgal, Keshav;Chatterjee, Aditi;Huang, Tai-Chung;Zhong, Jun;Wu, Xinyan;Shaw, Patrick G.;Freed, Donald;Zahari, Muhammad S.;Mukherjee, Kanchan K.;Shankar, Subramanian;Mahadevan, Anita;Lam, Henry;Mitchell, Christopher J.;Shankar, Susarla Krishna;Satishchandra, Parthasarathy;Schroeder, John T.;Sirdeshmukh, Ravi;Maitra, Anirban;Leach, Steven D.;Drake, Charles G.;Halushka, Marc K.;Prasad, T. S. Keshava;Hruban, Ralph H.;Kerr, Candace L.;Bader, Gary D.;Iacobuzio-Donahue, Christine A.;Gowda, Harsha;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
23.9
作者：
Magee, Jeffrey A.;Ikenoue, Tsuneo;Nakada, Daisuke;Lee, Jae Y.;Guan, Kun-Liang;Morrison, Sean J.
通讯作者：
Morrison, Sean J.
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere