Epigenetic control of natural killer cell maturation by histone H2A deubiquitinase, MYSM1.
Histone modifications play critical roles in regulating immunity; however, little is known about the epigenetic control of natural killer (NK) cell development. Here, we found that NK cell development is severely impaired in mice deficient in the histone H2A deubiquitinase MYSM1. We demonstrated that MYSM1 is required for NK cell maturation but not for NK lineage specification and commitment. We also found that MYSM1 intrinsically controls this NK cell maturation. Mechanistic studies revealed that the expression of transcription factor, inhibitor of DNA-binding protein (ID2), a critical factor for NK cell development, is impaired in Mysm1(-/-) NK cells. MYSM1 interacts with nuclear factor IL-3 (NFIL3, also known as E4BP4), a critical factor for mouse NK cell development, and the recruitment of nuclear factor Il-3 to the ID2 locus is dependent on MYSM1. Further, we observed that MYSM1 is involved in maintaining an active chromatin at the ID2 locus to promote NK cell development. Hence this study demonstrates the critical epigenetic regulation of NK cell development by the histone H2A deubiquitinase MYSM1 through the transcriptional control of transcription factors important for NK cell development.
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Vijayalakshmi
V
Nandakumar
Yuchia
Y
Chou
Linda
L
Zang
Xue F
XF
Huang
Si-Yi
SY
Chen
D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D010450:Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000276:immunology*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators; D014161:Transduction, Genetic; D064570:Ubiquitin-Specific Proteases
C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D007377:Interleukin-3; D015534:Trans-Activators; D010450:Endopeptidases; C570173:MYSM1 protein, mouse; D064570:Ubiquitin-Specific Proteases
NFIL3; histone deubiquitination