Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2
Recent studies have uncovered that non-coding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese ARS family and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between PITX2 and FAM241A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-seq and RT-qPCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while Foxc1 expression remained unchanged. ChIP-seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a significant downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) which is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence which is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent. 2.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
JCI insight - (2024) vom: 09. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jiang, Yizheng [VerfasserIn] |
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| Links: |
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| Themen: |
Genetic diseases |
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| Anmerkungen: |
Date Revised 09.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1172/jci.insight.177032 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370821297 |
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| 245 | 1 | 0 | |a Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2 |
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| 520 | |a Recent studies have uncovered that non-coding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese ARS family and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between PITX2 and FAM241A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-seq and RT-qPCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while Foxc1 expression remained unchanged. ChIP-seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a significant downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) which is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence which is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent. 2 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Genetic diseases | |
| 650 | 4 | |a Genetic variation | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Ophthalmology | |
| 700 | 1 | |a Peng, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Zhe |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Junping |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Zhengmao |e verfasserin |4 aut | |
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