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Taspase1 orchestrates fetal liver hematopoietic stem cell and vertebrae fates by cleaving TFIIA
Hidetaka Niizuma, … , Emily H. Cheng, James J. Hsieh
Hidetaka Niizuma, … , Emily H. Cheng, James J. Hsieh
Published June 22, 2021
Citation Information: JCI Insight. 2021;6(15):e149382. https://doi.org/10.1172/jci.insight.149382.
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Research Article Development Stem cells

Taspase1 orchestrates fetal liver hematopoietic stem cell and vertebrae fates by cleaving TFIIA

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Abstract

Taspase1, a highly conserved threonine protease encoded by TASP1, cleaves nuclear histone-modifying factors and basal transcription regulators to orchestrate diverse transcription programs. Hereditary loss-of-function mutation of TASP1 has recently been reported in humans as resulting in an anomaly complex syndrome, which manifests with hematological, facial, and skeletal abnormalities. Here, we demonstrate that Taspase1-mediated cleavage of TFIIAα-β, rather than of MLL1 or MLL2, in mouse embryos was required for proper fetal liver hematopoiesis and correct segmental identities of the axial skeleton. Homozygous genetic deletion of Taspase1 disrupted embryonic hematopoietic stem cell self-renewal and quiescence states and axial skeleton fates. Strikingly, mice carrying knockin noncleavable mutations of TFIIAα-β, a well-characterized basal transcription factor, displayed more pronounced fetal liver and axial skeleton defects than those with noncleavable MLL1 and MLL2, 2 trithorax group histone H3 trimethyl transferases. Our study offers molecular insights into a syndrome in humans that results from loss of TASP1 and describes an unexpected role of TFIIAα-β cleavage in embryonic cell fate decisions.

Authors

Hidetaka Niizuma, Adam C. Searleman, Shugaku Takeda, Scott A. Armstrong, Christopher Y. Park, Emily H. Cheng, James J. Hsieh

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Figure 4

Gtf2a1nc/nc hematopoietic stem cells exhibit overt fetal liver hematopoiesis defects.

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Gtf2a1nc/nc hematopoietic stem cells exhibit overt fetal liver hematopoi...
(A) Body weight and normalized fetal liver (FL) cellularity of 19 WT and 27 Gtf2a1nc/nc E14.5 FLs. Boxes contain the 25th to 75th percentiles of data sets, with 50th percentile center lines, and whiskers mark the 5th and 95th percentiles. Outliers are shown by dots. ***P < 0.001 by Mann-Whitney U test. (B) Images of E14.5 FLs of the indicated WT and Gtf2a1nc/nc embryos. Scale bar: 2 mm. (C and D) Quantification of hematopoietic stem and progenitor cells of E14.5 FLs by flow cytometry. (C) Representative dot plots. (D) The frequency of stem and progenitor cells in FLs. (E) The number of hematopoietic stem cells (HSCs) per FL. Data are shown as the mean ± SEM. **P < 0.01, ***P < 0.001 by Mann-Whitney U test (WT, n = 6; Gtf2a1nc/nc, n = 8).

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