Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Abstract Background Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN, in DS-associated transcriptional regulation and phenotypic modulation....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Biological Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40659-023-00474-x |
| _version_ | 1797398176645251072 |
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| author | Zhenglong Guo Yongchang Zhu Hai Xiao Ranran Dai Wenke Yang Wei Xue Xueying Zhang Bingtao Hao Shixiu Liao |
| author_facet | Zhenglong Guo Yongchang Zhu Hai Xiao Ranran Dai Wenke Yang Wei Xue Xueying Zhang Bingtao Hao Shixiu Liao |
| author_sort | Zhenglong Guo |
| collection | DOAJ |
| description | Abstract Background Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN, in DS-associated transcriptional regulation and phenotypic modulation. Methods We performed assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq) to explore the difference of chromatin accessibility between DS derived amniocytes (DSACs) and controls. We then combined the annotated differentially expressed genes (DEGs) and enriched transcriptional factors (TFs) targeting the promoter region from ATAC-seq results with the DEGs in RNA-seq, to identify key genes and pathways involved in alterations of biological processes and pathways in DS. Results Binding motif analysis showed a significant increase in chromatin accessibility of genes related to neural cell function, among others, in DSACs, which is primarily regulated by members of the activator protein-1 (AP-1) transcriptional factor family. Further studies indicated that MX Dynamin Like GTPase 1 (MX1), defined as one of the key effector genes of I-IFN, is a critical upstream regulator. Its overexpression induced expression of AP-1 TFs and mediated inflammatory response, thus leading to decreased cellular viability of DS cells. Moreover, treatment with specific AP-1 inhibitor T-5224 improved DS-associated phenotypes in DSACs. Conclusions This study demonstrates that MX1-mediated AP-1 activation is partially responsible for cellular dysfunction of DS. T-5224 effectively ameliorated DS-associated phenotypes in DSACs, suggesting it as a potential treatment option for DS patients. |
| first_indexed | 2024-03-09T01:22:00Z |
| format | Article |
| id | doaj.art-eade3ea0fdd74de884874d0f2de7b9da |
| institution | Directory Open Access Journal |
| issn | 0717-6287 |
| language | English |
| last_indexed | 2024-03-09T01:22:00Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Biological Research |
| spelling | doaj.art-eade3ea0fdd74de884874d0f2de7b9da2023-12-10T12:08:15ZengBMCBiological Research0717-62872023-12-0156111310.1186/s40659-023-00474-xIntegration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndromeZhenglong Guo0Yongchang Zhu1Hai Xiao2Ranran Dai3Wenke Yang4Wei Xue5Xueying Zhang6Bingtao Hao7Shixiu Liao8Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou UniversityHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou UniversityHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou UniversityCancer Research Institute, School of Basic Medical Sciences, Southern Medical UniversityHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou UniversityCancer Research Institute, School of Basic Medical Sciences, Southern Medical UniversityNHC Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and TechnologyHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou UniversityHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou UniversityAbstract Background Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN, in DS-associated transcriptional regulation and phenotypic modulation. Methods We performed assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq) to explore the difference of chromatin accessibility between DS derived amniocytes (DSACs) and controls. We then combined the annotated differentially expressed genes (DEGs) and enriched transcriptional factors (TFs) targeting the promoter region from ATAC-seq results with the DEGs in RNA-seq, to identify key genes and pathways involved in alterations of biological processes and pathways in DS. Results Binding motif analysis showed a significant increase in chromatin accessibility of genes related to neural cell function, among others, in DSACs, which is primarily regulated by members of the activator protein-1 (AP-1) transcriptional factor family. Further studies indicated that MX Dynamin Like GTPase 1 (MX1), defined as one of the key effector genes of I-IFN, is a critical upstream regulator. Its overexpression induced expression of AP-1 TFs and mediated inflammatory response, thus leading to decreased cellular viability of DS cells. Moreover, treatment with specific AP-1 inhibitor T-5224 improved DS-associated phenotypes in DSACs. Conclusions This study demonstrates that MX1-mediated AP-1 activation is partially responsible for cellular dysfunction of DS. T-5224 effectively ameliorated DS-associated phenotypes in DSACs, suggesting it as a potential treatment option for DS patients.https://doi.org/10.1186/s40659-023-00474-xDown syndromeAmniocytesATAC-seq and RNA-seqI-IFNMX1AP-1 |
| spellingShingle | Zhenglong Guo Yongchang Zhu Hai Xiao Ranran Dai Wenke Yang Wei Xue Xueying Zhang Bingtao Hao Shixiu Liao Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome Biological Research Down syndrome Amniocytes ATAC-seq and RNA-seq I-IFN MX1 AP-1 |
| title | Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome |
| title_full | Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome |
| title_fullStr | Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome |
| title_full_unstemmed | Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome |
| title_short | Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome |
| title_sort | integration of atac seq and rna seq identifies mx1 mediated ap 1 transcriptional regulation as a therapeutic target for down syndrome |
| topic | Down syndrome Amniocytes ATAC-seq and RNA-seq I-IFN MX1 AP-1 |
| url | https://doi.org/10.1186/s40659-023-00474-x |
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