GID complex regulates the differentiation of neural stem cells by destabilizing TET2

doi:10.1007/s11684-023-1007-9

Front. Med.

2023, Vol. 17

Issue (6) : 1204-1218 https://doi.org/10.1007/s11684-023-1007-9

GID complex regulates the differentiation of neural stem cells by destabilizing TET2

Meiling Xia^1,², Rui Yan², Wenjuan Wang², Meng Zhang², Zhigang Miao², Bo Wan²(

), Xingshun Xu^1,^2,³(

)

¹. Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
². Institute of Neuroscience, Soochow University, Suzhou 215006, China
³. Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou 215123, China

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Abstract

Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells (NSC), which rely on the precise regulation of gene expression. Ten-eleven translocation 2 (TET2) modulates gene expression by the hydroxymethylation of 5-methylcytosine in DNA as an important epigenetic factor and participates in the neuronal differentiation. Yet, the regulation of TET2 in the process of neuronal differentiation remains unknown. Here, the protein level of TET2 was reduced by the ubiquitin-proteasome pathway during NSC differentiation, in contrast to mRNA level. We identified that TET2 physically interacts with the core subunits of the glucose-induced degradation-deficient (GID) ubiquitin ligase complex, an evolutionarily conserved ubiquitin ligase complex and is ubiquitinated by itself. The protein levels of GID complex subunits increased reciprocally with TET2 level upon NSC differentiation. The silencing of the core subunits of the GID complex, including WDR26 and ARMC8, attenuated the ubiquitination and degradation of TET2, increased the global 5-hydroxymethylcytosine levels, and promoted the differentiation of the NSC. TET2 level increased in the brain of the Wdr26^+/− mice. Our results illustrated that the GID complex negatively regulates TET2 protein stability, further modulates NSC differentiation, and represents a novel regulatory mechanism involved in brain development.

Keywords TET2 GID complex neural stem cells differentiation of neurons

Corresponding Author(s): Bo Wan,Xingshun Xu

Just Accepted Date: 28 July 2023 Online First Date: 13 September 2023 Issue Date: 06 February 2024

Cite this article:

Meiling Xia,Rui Yan,Wenjuan Wang, et al. GID complex regulates the differentiation of neural stem cells by destabilizing TET2[J]. Front. Med., 2023, 17(6): 1204-1218.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1007-9
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1204

Fig.1 Ablation of Tet2 reduced the neural differentiation of NSC. (A,B) Representative immunofluorescence (IF) images (A) and relative quantification (B) of TUJ1⁺ immature neurons (green) in the DG of 2-month-old wild-type (WT) and Tet2 cKO mice. Scale bar, 50?μm; n = 4. (C,D) Representative IF images (C) and relative quantification (D) of SOX2⁺ NSC (green) in the DG of 2-month-old WT and Tet2 cKO mice. Scale bar, 50?μm; n = 4. (E,F) Representative IF images (E) and relative quantification (F) of PCNA⁺ proliferating NSC (green) in the DG of 2-month-old WT and Tet2 cKO mice. Scale bar, 50?μm; n = 4. (G,H) The neurospheres were extracted from E14.5-day-old WT and Tet2 cKO mice. After 5 days of incubation, neurosphere-derived single cells were cultured for 5 days to detect the number and diameters of neurospheres. After neurosphere-derived single cells were plated, the growth medium containing forskolin (1 μmol/L) and retina acid (1 μmol/L) was used to induce the differentiation of the NSC for 48 h for IF staining. Representative IF images (G) and relative quantification (H) of SOX2⁺KI67⁺ proliferating neurospheres (yellow). (I) Representative bright-field images of the second passage hippocampal neurospheres culture in vitro on day 5 and IF images of TUJ1⁺ immature neurons (green), and GFAP⁺ astrocytes (red) of WT and Tet2 cKO mice. Scale bar of bright-field images, 25?μm; scale bar of IF images, 50?μm; n = 3. (J,K) Quantification of the diameter (J) and relative number (K) of cultured neurospheres. (L) Quantification of relative TUJ1⁺ neurons after NSC differentiation was induced. Quantified data were normalized to the control group. The value was equal to 1. All data were presented as mean ± SEM. Unpaired two-tailed Student’s t-test was used. *P < 0.05; **P < 0.01.

Fig.2 Proteasome pathway is the main pathway that affects the stability of TET2. (A) The quantitative real-time PCR of Tet2 level before and after NSC differentiation; n = 5. (B,C) Representative Western blots (B) and quantitative analysis of TET2 (C) level before and after NSC differentiation; n = 4. (D,E) Representative Western blots (D) and quantitative analysis of FLAG-TET2 (E) in HEK293t cells. HEK293t cells were transfected with FLAG-TET2 for 24 h and then treated with cycloheximide (CHX; 50 µg/mL) alone or in combination with MG132 (10 µmol/L), Z-VAD-FMK (10 µmol/L), or calpeptin (20 µmol/L) for 12 h. Cell lysates were subjected to Western blotting with the FLAG antibody; n = 4. (F–I) Representative Western blots (F,H) and quantitative analysis of TET2 (G,I) in N2a (F,G) or HT22 cells (H,I). N2a or HT22 cells were treated with CHX (15 µg/mL for HT22 cells and 25 µg/mL for N2a cells) alone or in combination with MG132 (10 µmol/L), or Z-VAD-FMK (10 µmol/L), or calpeptin (20 µmol/L) for 12 h. Cell lysates were subjected to Western blotting with the TET2 antibody; n = 4. Quantified data were normalized to the control group. The value was equal to 1. All data were presented as mean ± SEM. Unpaired two-tailed Student’s t-test (A, C) and one-way ANOVA (E, G, I) were used. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Fig.3 TET2 interacts with GID complex subunits WDR26 and ARMC8. (A,B) Using the Metascape website for functional analysis based on the mass spectra of TET2 interacting proteins. (C,D) The list of GID complex subunits that could potentially interact with TET2 were sieved out by cluster analysis. Mouse FLAG-TET2 and HA-WDR26/HA-ARMC8 expression plasmids were co-transfected into HEK293t cells, and using anti-FLAG magnetic beads for extraneous immunoprecipitation. Co-immunoprecipitation (Co-IP) assays was used to validate interaction of HA-WDR26 (E) or HA-ARMC8 (F) with FLAG-TET2 in HEK293t cells. (G) Endogenous Co-IP experiments of TET2 with WDR26 and ARMC8 were using N2a cells, and immunoblotting with TET2, WDR26 and ARMC8 antibody.

Fig.4 TET2 and GID complex was highly expressed in neurons. (A–C) Representative images of SOX2⁺ (red) and NESTIN⁺ (green) NSC (A), MAP2⁺ (green) neurons (B) and GFAP⁺ (red) astrocytes (C). NSC and neurons were extracted from E14.5-day-old wild-type mice and astrocytes from 2-day-old mice. (D) Relative mRNA levels of TET family members and GID complex members in astrocytes, NSC, and neurons were examined; n = 5–6. Quantified data were normalized to the control group. The value was equal to 1. All data were presented as mean ± SEM. One-way ANOVA was used. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Fig.5 TET2-GID complex is involved in neuronal differentiation. (A) RT-PCR of TET family and GID complex members’ relative mRNA levels before and after NSC differentiation; n = 4. (B–E) Representative Western blots (B) and quantitative analysis of TET2 (C), WDR26 (D), and ARMC8 (E) in NSC before and after differentiation; n = 4. (F) RT-PCR of TET family and GID complex members’ relative mRNA levels before and after N2a cell differentiation; n = 4. (G–J) Representative Western blots (G) and quantitative analysis of TET2 (H), WDR26 (I), and ARMC8 (J) in N2a cells before and after differentiation; n = 4. (K) Representative Western blots of TET2, WDR26, and ARMC8 during N2a differentiation. NSC differentiation was induced by forskolin (1 μmol/L) and RA (1 μmol/L) for 48 h, and N2a cell differentiation was induced by RA (20 μmol/L) for 12 h. (L) Representative Western blots of TET2, WDR26, and ARMC8 in the hippocampi of mice from days 1, 7, 14, 21, and 30. Quantified data were normalized to the control group, and the value was equal to 1. All data were presented as mean ± SEM. Unpaired two-tailed Student’s t-test was used. *P < 0.05; **P < 0.01; ****P < 0.0001.

Fig.6 TET2 is the direct substrate of the GID complex. (A–C) Western blots confirmed the knockout of Armc8 (A), Wdr26 (B), or Tet2 (C) by sgRNAs in the N2a cells. (D,E) A rescue experiment was used to detect the effect of Armc8 KO on the degradation of TET2 with overexpression FLAG-ARMC8 plasmids in the Armc8 KO N2a cells. Wild-type (WT) N2a cells were transfected with vector plasmids (the first lane), and Armc8 KO N2a cells were transfected with vector or FLAG-ARMC8 plasmids (the second and third lanes). Representative Western blots (D) and quantitative analysis of TET2 and FLAG-ARMC8 (E); n = 3. (F,G) WT N2a cells were transfected with vector plasmids (the first lane), and the Wdr26 KO N2a cells were transfected with vector or HA-WDR26 plasmids (the second and third lanes). Representative Western blots (F) and quantitative analysis of TET2 and HA-WDR26 (G) with overexpression HA-WDR26 plasmids in the Wdr26 KO N2a cells; n = 3. (H) Representative Western blots of TET2 ubiquitination of control or ARMC8-overexpressed N2a cells. (I,J) Representative Western blots (I) and quantitative analysis (J) of control or Armc8 KO N2a cells, which were treated with 25 µg/mL cycloheximide (CHX) for different periods. (K) Representative Western blots of TET2 ubiquitination of control or WDR26-overexpressed N2a cells. (L,M) Representative Western blots (L) and quantitative analysis (M) of control or Wdr26-knockout N2a cells treated with 25 µg/mL CHX for different periods. (I, J, L and M) WT or Armc8 (I,J) or Wdr26 (L,M) knockout N2a cells were treated with 25 µg/mL CHX for different periods. The levels of the indicated proteins were examined by immunoblotting. Quantified data were normalized to the control group, and the value was equal to 1. All data were presented as mean ± SEM. One-way ANOVA was used. *P < 0.05; **P < 0.01.

Fig.7 TET2 protein increased in Wdr26 heterozygous knockout mice. (A–D) Representative Western blots (A) and quantitative analysis of TET1 (B), TET2 (C), and TET3 (D) in wild-type and Wdr26 heterozygous knockout mice; n = 3. Quantified data were normalized to the control group, and the value was equal to 1. All data were presented as mean ± SEM. Unpaired two-tailed Student’s t-test was used. *P < 0.05.

Fig.8 GID complex subunit deletion promotes the DNA 5-hydroxymethylation. (A,B and E) Representative 5hmC (A) and 5mC (B) dot blots and quantitative analysis (E) of wild-type (WT) and Armc8 KO N2a cells; n = 3. (C,D and F) Representative 5hmC (C) and 5mC (D) dot blots and quantitative analysis (F) of WT and Wdr26 KO N2a cells; n = 3. Quantified data were normalized to the control group, and the value was equal to 1. All data were presented as mean ± SEM. Two-way ANOVA was used. *P < 0.05.

Fig.9 GID complex subunit deletion promoted the process of neuronal differentiation. (A) Representative images of wild-type (WT), Armc8 KO, and Wdr26 KO N2a cells before and after differentiation. (B,C) Percentage of differentiated cells (B) and axon length (C) of N2a cells of WT and Wdr26 KO N2a cells; n = 3. (D, F) Western blots confirmed the knockdown of Armc8 (D) and Wdr26 (F) by sgRNAs in NSC. (E,G) RT-PCR of Tuj1 mRNA level of Armc8 (E) and Wdr26 (G) knockdown NSC after induced differentiation; n = 4. Quantified data were normalized to the control group, and the value was equal to 1. All data were presented as mean ± SEM. Unpaired two-tailed Student’s t-test (E,G) and two-way ANOVA (B,C) were used. *P < 0.05; **P < 0.01.

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