期刊
NATURE CELL BIOLOGY
卷 19, 期 6, 页码 626-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ncb3527
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资金
- NIH [R35CA197532, T32HL076139, K01DK093543, R03DK101665, R01DK111430]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institute of Higher Learning [TP2015003]
- 100-Talent Program of the Chinese Academy of Sciences [Y516C11851]
- Science and Technology Commission of Shanghai Municipality [14PJ1410000, 16ZR1448600]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RR140025]
- American Cancer Society [IRG-02-196]
- Harold C. Simmons Comprehensive Cancer Center at UT Southwestern
- American Society of Hematology Scholar Award
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 haematopoietic 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 signalling 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 haematologic defects associated with mitochondrial diseases and ageing.
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