The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors
© 2020 Zhang et al..
The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:295 |
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| Enthalten in: |
The Journal of biological chemistry - 295(2020), 7 vom: 14. Feb., Seite 1879-1888 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Chengfu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.10.2020 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA119.011163 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM305309293 |
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| 100 | 1 | |a Zhang, Chengfu |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 14.10.2020 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Zhang et al. | ||
| 520 | |a The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a chicken | |
| 650 | 4 | |a differentiation | |
| 650 | 4 | |a electroporation | |
| 650 | 4 | |a genetics | |
| 650 | 4 | |a neurobiology | |
| 650 | 4 | |a neurodevelopment | |
| 650 | 4 | |a neurodifferentiation | |
| 650 | 4 | |a oligodendrocyte | |
| 650 | 4 | |a spinal cord | |
| 650 | 7 | |a Co-Repressor Proteins |2 NLM | |
| 650 | 7 | |a Dnmt3a protein, mouse |2 NLM | |
| 650 | 7 | |a Homeobox Protein Nkx-2.2 |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a Nkx2-2 protein, mouse |2 NLM | |
| 650 | 7 | |a Tle3 protein, mouse |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Zebrafish Proteins |2 NLM | |
| 650 | 7 | |a nkx2.2b protein, zebrafish |2 NLM | |
| 650 | 7 | |a DNA (Cytosine-5-)-Methyltransferases |2 NLM | |
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| 650 | 7 | |a DNA Methyltransferase 3A |2 NLM | |
| 650 | 7 | |a EC 2.1.1.37 |2 NLM | |
| 650 | 7 | |a Hdac1 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 650 | 7 | |a Histone Deacetylase 1 |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 700 | 1 | |a Huang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zunyi |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Wenwen |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Mengsheng |e verfasserin |4 aut | |
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