ArticleThe Journal of clinical investigation2019
Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 59 citations in OpenAlex.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Enhancer Trajectories in Lineage Commitment: Regulatory Logic of States and Cooperation.Biomolecules · 2026Review
- Deletion of an enhancer that controls Wnt gene expression following tissue injury produces increased adipogenesis in regenerated muscle.Development (Cambridge, England) · 2025Article
- Signaling mechanisms and cis -regulatory control of Samd14 in erythroid regeneration.Current opinion in hematology · 2025Review
- Hematological phenotypes in GATA2 deficiency syndrome arise from aging, maladaptation to proliferation, and somatic events.Blood advances · 2025Article
- Dual mechanism of inflammation sensing by the hematopoietic progenitor genome.Science advances · 2025Article
- GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome.Blood cancer journal · 2025Article
- A screen for regeneration-associated silencer regulatory elements in zebrafish.Developmental cell · 2024Article
- Pathogenic GATA2 genetic variants utilize an obligate enhancer mechanism to distort a multilineage differentiation program.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- C and G are frequently mutated into T and A in coding regions of human genes.Molecular genetics and genomics : MGG · 2024Article
- Gata2 noncoding genetic variation as a determinant of hematopoietic stem/progenitor cell mobilization efficiency.Blood advances · 2023Article
- Defining a cohort of anemia-activated cis elements reveals a mechanism promoting erythroid precursor function.Blood advances · 2023Article
- A novel GATA2 distal enhancer mutation results in MonoMAC syndrome in 2 second cousins.Blood advances · 2023Article
- Role of the pioneer transcription factor GATA2 in health and disease.Journal of molecular medicine (Berlin, Germany) · 2023Review
- IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma.NPJ genomic medicine · 2023Article
- Myc beyond Cancer: Regulation of Mammalian Tissue Regeneration.Pathophysiology : the official journal of the International Society for Pathophysiology · 2023Review
- Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.Nature genetics · 2023Article
- Restricting genomic actions of innate immune mediators on fetal hematopoietic progenitor cells.iScience · 2023Article
- Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks.The Journal of clinical investigation · 2023Article
- Germline and somatic drivers in inherited hematologic malignancies.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.