Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer
| Autor: | Yun Zhou, Jing Zhang, Charu Mehta, Kirby D. Johnson, Inga Hofmann, Jun Wu, Sunduz Keles, Kyunghee Choi, Alexandra A. Soukup, Peng Liu, Emery H. Bresnick, Miao Cao, Ye Zheng |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
GATA2 Deficiency Mutant Biology 03 medical and health sciences Mice 0302 clinical medicine Germline mutation Animals Humans Regeneration Progenitor cell Nucleotide Motifs Enhancer Germ-Line Mutation GATA2 Myeloid leukemia General Medicine Mice Mutant Strains Cell biology Hematopoiesis GATA2 Transcription Factor Haematopoiesis 030104 developmental biology Enhancer Elements Genetic 030220 oncology & carcinogenesis Stem cell Research Article |
| Zdroj: | The Journal of clinical investigation. 129(3) |
| ISSN: | 1558-8238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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