Abstract
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.
MeSH terms
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Acetylation
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Animals
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Erythropoiesis*
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Gene Expression Profiling / methods
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Hematopoietic Stem Cells / enzymology*
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High Mobility Group Proteins / genetics
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High Mobility Group Proteins / metabolism
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Histones / metabolism
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Mice, Knockout
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Mitochondria / enzymology*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Organelle Biogenesis*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phenotype
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Prohibitins
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Protein Biosynthesis*
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Proteomics / methods
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RNA / genetics
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RNA / metabolism
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Mitochondrial
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Receptors, Erythropoietin / genetics
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Receptors, Erythropoietin / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
Substances
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DNA-Binding Proteins
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High Mobility Group Proteins
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Histones
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Mitochondrial Proteins
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Multiprotein Complexes
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PHB2 protein, human
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Phb2 protein, mouse
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Prohibitins
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RNA, Messenger
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RNA, Mitochondrial
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Receptors, Erythropoietin
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Repressor Proteins
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TFAM protein, human
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Tfam protein, mouse
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Transcription Factors
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RNA
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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Pten protein, mouse