ABSTRACT
Innate lymphoid cells (ILCs) exert important roles in host defense, tissue repair and inflammatory diseases. However, how ILC lineage specification is regulated remains largely elusive. Here we identify that circular RNA circTmem241 is highly expressed in group III innate lymphoid cells (ILC3s) and their progenitor cells. CircTmem241 deficiency impairs ILC3 commitment and attenuates anti-bacterial immunity. Mechanistically, circTmem241 interacts with Nono protein to recruit histone methyltransferase Ash1l onto Elk3 promoter in ILC progenitor cells (ILCPs). Ash1l-mediated histone modifications on Elk3 promoter enhance chromatin accessibility to initiate Elk3 transcription. Of note, circTmem241-/-, Nono-/- and Ash1l-/- ILCPs display impaired ILC3 differentiation, while Elk3 overexpression rescues ILC3 commitment ability. Finally, circTmem241-/-Elk3-/- mice show lower numbers of ILC3s and are more susceptible to bacterial infection. We reveal that the circTmem241-Nono-Ash1l-Elk3 axis is required for the ILCP differentiation into ILC3P and ILC3 maturation, which is important to manipulate this axis for ILC development on treatment of infectious diseases.
Subject(s)
Immunity, Innate , Lymphocytes , Membrane Proteins/genetics , Proto-Oncogene Proteins c-ets/metabolism , Animals , Cell Differentiation , DNA-Binding Proteins/genetics , Histone-Lysine N-Methyltransferase , Lymphocytes/metabolism , Mice , RNA, Circular , Transcription Factors/metabolismABSTRACT
Neutrophils are derived from bone marrow hematopoietic stem cells (HSCs) and are the largest population among circulating white blood cells in humans, acting as the first line of defense against invading pathogens. Whether neutrophils can be generated by transdifferentiation strategies is unknown. Here, we show that thymidine induces the conversion of mouse fibroblasts to neutrophils. Induced neutrophils (iNeus) showed antibacterial effects and did not undergo malignant transformation in vivo. Importantly, iNeu transplantation cured neutropenia in mice in vivo. Mechanistically, thymidine mediates iNeu conversion by enhancing Tet3 activity. Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils. Therefore, the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.Fibroblasts; Neutrophils; Thymidine; Transdifferentiation; Tet3.
Subject(s)
Dioxygenases , Neutropenia , Animals , Dioxygenases/metabolism , Fibroblasts/metabolism , Humans , Mice , Neutropenia/metabolism , Neutropenia/pathology , Neutrophils/metabolism , Regulatory Factor X1/metabolism , Thymidine/metabolismABSTRACT
Group 3 innate lymphoid cells (ILC3s) play critical roles in innate immunity and gut homeostasis. However, how ILC3 homeostasis is regulated remains elusive. Here, we identified a novel circular RNA, circZbtb20, that is highly expressed in ILC3s and required for their maintenance and function. CircZbtb20 deletion causes reduced ILC3 numbers, increasing susceptibility to C. rodentium infection. Mechanistically, circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA, leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability. Nr4a1 initiates Notch2 signaling activation, which contributes to the maintenance of ILC3 homeostasis. Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection. Thus, our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.
Subject(s)
Adenosine/analogs & derivatives , AlkB Homolog 5, RNA Demethylase/metabolism , Demethylation , Homeostasis , Immunity, Innate/genetics , Lymphocytes/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , RNA, Circular/metabolism , Adenosine/metabolism , Animals , Cell Proliferation , Cell Survival , Gastrointestinal Tract/immunology , Mice, Knockout , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Protein Binding , RNA Stability , RNA, Circular/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, Notch2/metabolism , Signal TransductionABSTRACT
Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3-/-Rag1-/- and circKcnt2-/-Rag1-/- mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis.
Subject(s)
Colitis/immunology , Colitis/metabolism , Lymphocytes/metabolism , Potassium Channels, Sodium-Activated/metabolism , RNA, Circular/metabolism , Animals , Colitis/pathology , DNA-Binding Proteins/genetics , Disease Models, Animal , Female , Homeodomain Proteins/genetics , Homeostasis , Humans , Immunity, Innate , Inflammation/immunology , Inflammation/pathology , Intestines/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Potassium Channels, Sodium-Activated/genetics , RNA, Circular/genetics , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Transcription Factors/geneticsABSTRACT
Lgr5+ intestinal stem cells (ISCs) exhibit self-renewal and differentiation features under homeostatic conditions, but the mechanisms controlling Lgr5 + ISC self-renewal remain elusive. Here, we show that the chromatin remodeler SRCAP is highly expressed in mouse intestinal epithelium and ISCs. Srcap deletion impairs both self-renewal of ISCs and intestinal epithelial regeneration. Mechanistically, SRCAP recruits the transcriptional regulator REST to the Prdm16 promoter and induces expression of this transcription factor. By activating PPARδ expression, Prdm16 in turn initiates PPARδ signaling, which sustains ISC stemness. Rest or Prdm16 deficiency abrogates the self-renewal capacity of ISCs as well as intestinal epithelial regeneration. Collectively, these data show that the SRCAP-REST-Prdm16-PPARδ axis is required for self-renewal maintenance of Lgr5 + ISCs.
Subject(s)
Adenosine Triphosphatases/metabolism , Intestinal Mucosa/enzymology , Signal Transduction , Stem Cells/enzymology , Adenosine Triphosphatases/genetics , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , HEK293 Cells , Humans , Intestinal Mucosa/cytology , Mice , Mice, Transgenic , Promoter Regions, Genetic , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Stem Cells/cytology , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Innate lymphoid cells (ILCs) play critical roles in defending infections and maintaining mucosal homeostasis. All ILCs arise from common lymphoid progenitors (CLPs) in bone marrow. However, how CLPs stratify and differentiate into ILC lineages remains elusive. Here, we showed that Yeats4 is highly expressed in ILCs and their progenitors. Yeats4 conditional KO in the hematopoietic system causes decreased numbers of ILCs and impairs their effector functions. Moreover, Yeats4 regulates α4ß7 + CLP differentiation toward common helper ILC progenitors (CHILPs). Mechanistically, Yeats4 recruits the Dot1l-RNA Pol II complex onto Lmo4 promoter through recognizing H3K27ac modification to initiate Lmo4 transcription in α4ß7 + CLPs. Additionally, Lmo4 deficiency also impairs ILC lineage differentiation and their effector functions. Collectively, the Yeats4-Lmo4 axis is required for ILC lineage commitment.