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.

• Authors: Alexandra A Soukup, Ye Zheng, Charu Mehta, Jun Wu, Peng Liu, Miao Cao, Inga Hofmann, Yun Zhou, Jing Zhang, Kirby D Johnson, Kyunghee Choi, Sunduz Keles, Emery H Bresnick
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 3 Pg. 1180-1192 (03 01 2019) ISSN: 1558-8238 [Electronic] United States
• PMID: 30620726 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)

Chemical References

• GATA2 Transcription Factor
• Gata2 protein, mouse

Topics

• Animals
• Enhancer Elements, Genetic
• GATA2 Deficiency (genetics, metabolism)
• GATA2 Transcription Factor (genetics, metabolism)
• Germ-Line Mutation
• Hematopoiesis (genetics)
• Humans
• Mice
• Mice, Mutant Strains
• Nucleotide Motifs
• Regeneration (genetics)