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Long noncoding RNA lncKdm2b is required for ILC3 maintenance by initiation of Zfp292 expression

Nature Immunology volume 18, pages 499–508 (2017)Cite this article

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Abstract

Innate lymphoid cells (ILCs) communicate with other hematopoietic and nonhematopoietic cells to regulate immunity, inflammation and tissue homeostasis. How ILC lineages develop and are maintained remains largely unknown. In this study we observed that a divergent long noncoding RNA (lncRNA), lncKdm2b, was expressed at high levels in intestinal group 3 ILCs (ILC3s). LncKdm2b deficiency in the hematopoietic system led to reductions in the number and effector functions of ILC3s. LncKdm2b expression sustained the maintenance of ILC3s by promoting their proliferation through activation of the transcription factor Zfp292. Mechanistically, lncKdm2b recruited the chromatin organizer Satb1 and the nuclear remodeling factor (NURF) complex onto the Zfp292 promoter to initiate its transcription. Deletion of Zfp292 or Bptf also abrogated the maintenance of ILC3s, leading to susceptibility to bacterial infection. Therefore, our findings reveal that lncRNAs may represent an additional layer of regulation of ILC development and function.

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Figure 1: LncKdm2b deficiency impairs the maintenance and effector functions of ILC3s.
Figure 2: LncKdm2b knockout suppresses ILC3 proliferation.
Figure 3: LncKdm2b associates with Satb1.
Figure 4: LncKdm2b activates Zfp292 expression through association with Satb1.
Figure 5: LncKdm2b recruits Satb1 and the NURF complex onto the Zfp292 promoter to trigger its expression.
Figure 6: Zfp292 deficiency impairs ILC3 maintenance and effector functions.

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Acknowledgements

We thank D.R. Littman (New York University, New York, New York, USA) for providing pMIGR plasmid, and P. Zhu (Institute of Biophysics, CAS, Beijing, China) for pcDNA4/TO-mSatb1 plasmid. C. rodentium was a gift from B. Ge (Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China). We thank J. Li (Cnkingbio Company Ltd., Beijing, China) for technical support. We also thank S. Meng, D. Fan, X. Wu, L. Zhou, Y. Teng and J. Jia for technical support. This work was supported by the National Natural Science Foundation of China (grants 91640203, 31530093, and 91419308 to Z.F.; 31470864 and 31670886 to B.Y.; and 31601189 to X.Z.) and the Strategic Priority Research Programs of the Chinese Academy of Sciences (grants XDB19030203 and XDA12020219 to Z.F.).

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  1. Benyu Liu, Buqing Ye, Liuliu Yang and Xiaoxiao Zhu: These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Benyu Liu, Buqing Ye, Liuliu Yang, Guanling Huang, Pingping Zhu, Ying Du, Jiayi Wu, Xiwen Qin & Zusen Fan

  2. University of Chinese Academy of Sciences, Beijing, China

    Benyu Liu, Liuliu Yang, Guanling Huang, Jiayi Wu, Xiwen Qin, Runsheng Chen, Yong Tian & Zusen Fan

  3. Key Laboratory of RNA Biology of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Xiaoxiao Zhu, Runsheng Chen & Yong Tian

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Contributions

B.L. designed and conducted experiments, analyzed data and wrote the paper; B.Y. carried out experiments and analyzed data; L.Y. and X.Z. constructed plasmids and established mouse tools; G.H., P. Z., J.W., Y.D. and X.Q. analyzed data; R.C. initiated the study and analyzed data; Y.T. designed animal experiments and analyzed data; and Z.F. initiated the study and organized, designed, and wrote the paper.

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Correspondence to Runsheng Chen, Yong Tian or Zusen Fan.

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Integrated supplementary information

Supplementary Figure 1 Construction of lncKdm2b–RFP reporter and lncKdm2b-knockout mice.

(a) ILC3s (Lin−CD45loCD90hi) were isolated from small intestines, followed by immunofluorescence staining. LncKdm2b was detected by RNA fluorescence in situ hybridization (RNA-FISH). Green: lncKdm2b probe or scramble probe; red: CD127 or rat IgG2a-κ; purple: CD45 or rat IgG2b-κ. Nuclei were counterstained by DAPI. Scale bar, 5 μm. (b) Strategies for construction of lncKdm2bflox/flox and lncKdm2bRFP mice. (c) Total RNA from BM cells of lncKdm2bflox/flox or lncKdm2bflox/flox;Vav-Cre mice were extracted, followed by RNA hybridization. LncKdm2b specific probe was labeled with biotin. 18S RNA served as a loading control. (d,e) Analysis of ILC1s (d) and ILC2s (e) in small intestines from lncKdm2bflox/flox or lncKdm2bflox/flox;Vav-Cre mice by FACS. ILC1s were gated on CD3ɛ−CD45+NK1.1+NKp46+ and ILC2s were gated on Lin−Thy1.2+CD25+KLRG1+ST2+. n=6 for each group. (f,g) Analysis of NK cells in spleen (f) and ILC1s in liver (g) from lncKdm2bflox/flox;Vav-Cre− or lncKdm2bflox/flox;Vav-Cre+ mice. NK cells were gated on NKp46+NK1.1+. ILC1s were gated on CD3ɛ−DX5−TCRβ−NK1.1+CD49a+. n=6 for each group. (h) Total RNAs were extracted from ILC3s derived from lncKdm2bflox/flox or lncKdm2bflox/floxRorc-Cre mice, followed by analysis of lncKdm2b expression with RT-qPCR. (i) Numbers of NKp46+ ILC3s, CD4+ ILC3s and CD4− ILC3s in lncKdm2b+/+ and lncKdm2b-/- mice were calculated and shown as means±SD. n=6 per group. (j,k) LncKdm2bflox/flox and lncKdm2bflox/floxRorc-Cre mice were infected with C. rodentium. 6 days later, bacterial counts (CFUs) in feces (j) and colon length (k) were measured. n=6 for each group. (l) LPLs were isolated from lncKdm2b+/+ and lncKdm2b-/- mice post C. rodentium infection, and stimulated with IL-23 for 4 h. Then IL-22+ ILC3s were analyzed by FACS. (m) Secreted IL-22 protein by LPLs as in l was tested by ELISA after stimulated with IL-23 for 24h. n=6 each group. *p<0.01 and **p<0.001 by two-tailed Student’s t test. All data are representative of three independent experiments.

Supplementary Figure 2 LncKdm2b interacts with Sabt1.

(a) BrdU+ ILC3s (Lin−CD45+CD127+RORγt+) were analyzed by FACS. n=6 for each group. (b) Percentages of total ILC3s (Lin−CD45.2+CD127+RORγt+) in chimeras were checked by FACS. n=6 for each group. (c) Expression levels of lncKdm2b neighboring genes in lncKdm2b+/+ and lncKdm2b−/-ILC3s were detected by RT-qPCR. Data were normalized to endogenous Actb and shown as means ± SD. (d) Identification of Satb1 as an lncKdm2b binding protein. Satb1 protein sequences were identified by LTQ Orbitrap XL. (e) Relative mRNA levels of Zfp292 were examined by real-time qPCR. Fold changes were normalized to endogenous Actb. (f) Enrichment of RNA pol II on Zfp292 promoter in lncKdm2b+/+ and lncKdm2b-/- ILC3s. Nuclei were extracted from lncKdm2b+/+ or lncKdm2b-/-ILC3s, followed by ChIP-qPCR assays. (g) Generation of Satb1-/- mice. The schematic diagram of Satb1 KO construction by CRISPR/Cas9 technology (upper left). Frameshift of Satb1 gene was confirmed by DNA sequencing (lower left). Satb1 deletion was validated by immunoblotting (right panel). *p<0.01 by two-tailed Student’s t test. All data are representative of three independent experiments.

Supplementary Figure 3 Sabt1 interacts with the NURF complex.

(a) Identification of Bptf and Snf2l as Satb1 binding proteins. Bptf and Snf2l protein sequences were identified by LTQ Orbitrap XL. (b) Generation of Zfp292-/- mice. The schematic diagram of Satb1 KO construction by CRISPR/Cas9 technology (upper left). Frameshift of Zfp292 gene was confirmed by DNA sequencing (lower left). Zfp292 deletion was verified by immunoblotting (right panel). (c) LPLs from Zfp292+/+ and Zfp292-/- mice were isolated and stimulated with IL-23 for 4 h. Numbers of IL-22+ ILC3s were examined by FACS. *p<0.01 by two-tailed Student’s t test. All data are representative of three independent experiments.

Supplementary Figure 4 Deletion of Sabt1 or Bptf leads to reduced numbers of ILC3s.

(a,b) Percentages (a) and numbers (b) of ILC3s in small intestines derived from Satb1+/+ and Satb1-/- mice. Percentages of indicated cells were calculated and shown at right panel (a). n=6 per group. (c,d) Percentages (c) and numbers (d) of ILC3s in small intestines derived from Bptfflox/flox and Bptfflox/floxRorc-Cre mice. Percentages of indicated cells were calculated and shown at right panel (c). n=6 per group. (e) Bptfflox/flox and Bptfflox/floxRorc-Cre mice were infected with C. rodentium (5x109 CFUs per mouse). 6 days later, bacterial counts (CFUs) in feces were measured. n=6 for each group. (f) Bptfflox/floxRorc-Cre− and Bptfflox/floxRorc-Cre+ mice were infection with C. rodentium (5x109 CFUs per mouse) for 6 days, followed by H&E staining for colons. Scale bar, 50 μm. (g) 1x106 CD45.1 BM cells with 1x106 CD45.2 LPLs from WT or TKO mice infected with Zfp292 expressing retroviral were transplanted into lethally irradiated CD45.1 recipients. Percentages of ILC3s derived from CD45.2+ donors were analyzed by FACS. n=6 for each group. (h) Numbers of ILC3s as in g were analyzed by FACS. n=6 for each group. (i) Percentages of Ki67+ ILC3s in Zfp292+/+, lncKdm2b overexpression in Zfp292+/+ or Zfp292-/- LPLs were examined by FACS. n=6 for each group. *p<0.01 and **p<0.001 by two-tailed Student’s t test. All data are representative of at least three independent experiments.

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Liu, B., Ye, B., Yang, L. et al. Long noncoding RNA lncKdm2b is required for ILC3 maintenance by initiation of Zfp292 expression. Nat Immunol 18, 499–508 (2017). https://doi.org/10.1038/ni.3712

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