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Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.

ABSTRACT: The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ?40-fold in PTPMT1 knockout mice. Reintroduction of wild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondrial localization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analyses demonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositol phosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrial uncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoid progenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucial role of PTPMT1 in the metabolic regulation of HSC function.

SUBMITTER: Yu WM

PROVIDER: S-EPMC3632072 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.

Yu Wen-Mei WM Liu Xia X Shen Jinhua J Jovanovic Olga O Pohl Elena E EE Gerson Stanton L SL Finkel Toren T Broxmeyer Hal E HE Qu Cheng-Kui CK

Cell stem cell 20130101 1

The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ∼40-fold in PTPMT1 knockout mice. Reintroduction of wi ...[more]

PMID: 23290137

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Project description:Hematopoietic stem cells provide life-long production of blood cells and undergo self-renewal division in order to sustain the stem cell pool. Homeostatic maintenance of hematopoietic stem cell pool and blood cell production is vital for the organism to survive. We previously reported that latexin is a negative regulator of hematopoietic stem cells in mice. Its natural variation in the expression is inversely correlated with hematopoietic stem cell number. However, the molecular mechanisms regulating latexin transcription remain largely unknown, and the genetic factors contributing to its natural variation are not clearly defined. Here we discovered a chromatin protein, high-mobility group protein B2, as a novel transcriptional suppressor of latexin by using DNA pull-down and mass spectrometry. High-mobility group protein B2 knockdown increases latexin expression at transcript and protein levels, and decreases hematopoietic stem cell number and regeneration capacity in vivo Concomitant blockage of latexin activation significantly reverses these phenotypic changes, suggesting that latexin is one of the downstream targets and functional mediators of high-mobility group protein B2. We further identified a functional single nucleotide polymorphism, rs31528793, in the latexin promoter that binds to high-mobility group protein B2 and affects the promoter activity. G allelic variation in rs31528793 associates with the higher latexin expression and lower hematopoietic stem cell number, whereas C allele indicates the lower latexin expression and higher stem cell number. This study reveals for the first time that latexin transcription is regulated by both transacting (high-mobility group protein B2) and cis-acting (single nucleotide polymorphism rs31528793) factors. It uncovers the functional role of naturally occurring genetic variants, in combination with epigenetic regulator, in determining differential gene expression and phenotypic diversity in the hematopoietic stem cell population.

Dataset Information

Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.

Publications

Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.

Similar Datasets

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