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Cited by 15Down syndrome and intellectual disability researchGenomics and Chromatin Dynamicsinterferon and immune responses

Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome

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Guo, Zhenglong, Zhu, Yongchang, Xiao, Hai, Dai, Ranran, Yang, Wenke, Xue, Wei, Zhang, Xueying, Hao, Bingtao +1 more·2023·Biological Research
DOI 10.1186/s40659-023-00474-xPMC PMC10709892
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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.

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  • These findings underscore a global epigenetic rewiring beyond localized chromosomal effects, aligning with prior observations of genomewide Ts21 chromatin reorganization.

    “These findings underscore a global epigenetic rewiring beyond localized chromosomal effects, aligning with prior observations of genomewide Ts21 chromatin reorganization (24-26).”

    From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [25]

  • AP-1 complex is a dimeric protein assembly critical for immune regulation and a recently identified Ts21 therapeutic target.

    “Module 8 was also highly enriched for targets of the transcription factor AP-1 complex, a dimeric protein assembly critical for immune regulation and a recently identified Ts21 therapeutic target (25) (Fig. 6M).”

    From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [25]

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Authors
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S.
Affiliations
  • Henan University (CN)
  • Zhengzhou University (CN)
  • Southern Medical University (CN)
Corresponding author
  • Hao, Bingtao
  • Liao, Shixiu
ORCID
Venue
Biological Research
Publisher
Springer Science and Business Media LLC
Published
2023-12-09
Volume
56
Issue
1
Pages
67-67
ISSN
  • 0716-9760 (ISSN-L)
  • 0717-6287
DOI
10.1186/s40659-023-00474-x
PMC
PMC10709892
OpenAlex
W4389508730
Cited by
15
References
57
Citations by year
2026: 7 · 2025: 4 · 2024: 4
FWCI
3.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Major Projects Jointly Constructed by Henan Province and Ministry of Science and Technology (SBGJ202101003)
  • Young talents of Health Science and Technology Innovation in Henan Province (YXKC2021002, YQRC2023010)
  • Open Research Fund of National Health Commission Key Laboratory of Birth Defects Prevention & Henan Key Laboratory of Population Defects Prevention (ZD202304)
  • Natural Science Foundation of Henan Province (232300421121, 232300421281)
  • National Natural Science Foundation of China (32300627)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
Down syndrome, MX1, AP-1 transcription factor, type I interferon, chromatin accessibility, transcriptional regulation, T-5224, amniocytes, inflammation, therapeutic target
MeSH terms
Chromatin Immunoprecipitation Sequencing, RNA-Seq, Benzophenones, Chromatin, Down Syndrome, Humans, Isoxazoles, Transcription Factor AP-1, Myxovirus Resistance Proteins

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