Background: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality.
Objective: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome.
Methods: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed.
Results: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages.
Conclusion: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.
Keywords: Immunologic deficiency syndromes; NLR family; autoinflammatory diseases; chemotaxis; gain-of-function mutation; hereditary; inflammasomes; interferons; neomorphic mutation; pyrin domain-containing 3 protein.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon.Blood. 2001 May 1;97(9):2561-7. doi: 10.1182/blood.v97.9.2561. Blood. 2001. PMID: 11313242
Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon.J Exp Med. 1999 Jun 7;189(11):1847-52. doi: 10.1084/jem.189.11.1847. J Exp Med. 1999. PMID: 10359588 Free PMC article.
C/EBPε ΔRS derived from a neutrophil-specific granule deficiency patient interacts with HDAC1 and its dysfunction is restored by trichostatin A.Biochem Biophys Res Commun. 2019 Aug 13;516(1):293-299. doi: 10.1016/j.bbrc.2019.06.130. Epub 2019 Jun 27. Biochem Biophys Res Commun. 2019. PMID: 31256937
The Relationship between NALP3 and Autoinflammatory Syndromes.Int J Mol Sci. 2016 May 13;17(5):725. doi: 10.3390/ijms17050725. Int J Mol Sci. 2016. PMID: 27187378 Free PMC article. Review.
Role of the Leucine Zipper Domain of CCAAT/ Enhancer Binding Protein-Epsilon (C/EBPε) in Neutrophil-Specific Granule Deficiency.Crit Rev Immunol. 2016;36(4):349-358. doi: 10.1615/CritRevImmunol.2017019385. Crit Rev Immunol. 2016. PMID: 28322138 Review.
Cited by 1 article
Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases.Front Immunol. 2019 Oct 29;10:2448. doi: 10.3389/fimmu.2019.02448. eCollection 2019. Front Immunol. 2019. PMID: 31736939 Free PMC article. Review.