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Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer.


ABSTRACT: The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA-2 physiological activities necessitate that it be strictly regulated, and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans. Since mechanisms underlying how GATA2 enhancer disease mutations impact hematopoiesis and pathology are unclear, we generated mouse models of the enhancer mutations. While a multi-motif mutant was embryonically lethal, a single-nucleotide Ets motif mutant was viable, and steady-state hematopoiesis was normal. However, the Ets motif mutation abrogated stem/progenitor cell regeneration following stress. These results reveal a new mechanism in human genetics, in which a disease predisposition mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2-dependent pathogenesis.

SUBMITTER: Soukup AA 

PROVIDER: S-EPMC6391105 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer.

Soukup Alexandra A AA   Zheng Ye Y   Mehta Charu C   Wu Jun J   Liu Peng P   Cao Miao M   Hofmann Inga I   Zhou Yun Y   Zhang Jing J   Johnson Kirby D KD   Choi Kyunghee K   Keles Sunduz S   Bresnick Emery H EH  

The Journal of clinical investigation 20190211 3


The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA-2 physiological activities necessitate that it be strictly regulated, and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-eleme  ...[more]

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