Physiological role and mechanisms of action for a long noncoding haplotype region Article Swipe
Hong Xue
,
Manoj K. Mishra
,
Yong Liu
,
Pengyuan Liu
,
Michael Grzybowski
,
Rajan Pandey
,
Kristie Usa
,
Mark A. Vanden Avond
,
Niharika Bala
,
Abdel A. Alli
,
Allen W. Cowley
,
Qiongzi Qiu
,
Andrew S. Greene
,
Sridhar Rao
,
Caitlin C. O’Meara
,
Aron M. Geurts
,
Mingyu Liang
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.05.15.594413
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.05.15.594413
Most common sequence variants associated with human traits are in noncoding regions of the genome, form haplotypes with other noncoding variants, and exhibit small effect sizes in the general population. Determining the physiological roles and mechanisms of action for these noncoding variants, particularly large haplotypes containing multiple variants, is both critical and challenging. To address this challenge, we developed an approach that integrates physiological studies in genetically engineered and phenotypically permissive animal models, precise editing of large haplotypes in human induced pluripotent stem cells (hiPSCs), and targeted chromatin conformation analysis. We applied this approach to examine the blood pressure associated rs1173771 locus, which includes a haplotype containing 11 single nucleotide polymorphisms (SNPs) spanning 17.4 kbp. Deleting the orthologous noncoding region in the genome of the Dahl salt-sensitive rat attenuated the salt-induced increase in systolic blood pressure by nearly 10 mmHg. This attenuation of hypertension appeared to be mediated by upregulation of the adjacent gene Npr3 (natriuretic peptide receptor 3) in arteries, enhancing vasodilation. The blood pressure-elevating and -lowering haplotypes were precisely reconstituted in hiPSCs using an efficient, two-step genome editing technique. The blood pressure-elevating haplotype decreased NPR3 expression in endothelial cells and vascular smooth muscle cells derived from the edited, isogenic hiPSCs. The influence of the haplotype was partially recapitulated by the sentinel SNP rs1173771. Additionally, the blood pressure-elevating haplotype showed significantly greater chromatin interactions with the NPR3 promoter region. This study illustrates the feasibility of ascertaining the physiological roles and mechanisms of action for large noncoding haplotypes. Our efficient, integrated, and targeted approach can be applied to investigate other noncoding variants.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2024.05.15.594413
- https://www.biorxiv.org/content/biorxiv/early/2024/05/18/2024.05.15.594413.full.pdf
- OA Status
- green
- Cited By
- 5
- References
- 36
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4397293180
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4397293180Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2024.05.15.594413Digital Object Identifier
- Title
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Physiological role and mechanisms of action for a long noncoding haplotype regionWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2024Year of publication
- Publication date
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2024-05-18Full publication date if available
- Authors
-
Hong Xue, Manoj K. Mishra, Yong Liu, Pengyuan Liu, Michael Grzybowski, Rajan Pandey, Kristie Usa, Mark A. Vanden Avond, Niharika Bala, Abdel A. Alli, Allen W. Cowley, Qiongzi Qiu, Andrew S. Greene, Sridhar Rao, Caitlin C. O’Meara, Aron M. Geurts, Mingyu LiangList of authors in order
- Landing page
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https://doi.org/10.1101/2024.05.15.594413Publisher landing page
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https://www.biorxiv.org/content/biorxiv/early/2024/05/18/2024.05.15.594413.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2024/05/18/2024.05.15.594413.full.pdfDirect OA link when available
- Concepts
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Haplotype, Action (physics), Biology, Evolutionary biology, Genetics, Computational biology, Neuroscience, Gene, Genotype, Physics, Quantum mechanicsTop concepts (fields/topics) attached by OpenAlex
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5Total citation count in OpenAlex
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2025: 1, 2024: 4Per-year citation counts (last 5 years)
- References (count)
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36Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.containing | 46, 107 |
| abstract_inverted_index.efficient, | 177, 250 |
| abstract_inverted_index.engineered | 68 |
| abstract_inverted_index.expression | 188 |
| abstract_inverted_index.haplotypes | 17, 45, 78, 169 |
| abstract_inverted_index.integrates | 63 |
| abstract_inverted_index.mechanisms | 36, 242 |
| abstract_inverted_index.nucleotide | 110 |
| abstract_inverted_index.permissive | 71 |
| abstract_inverted_index.rs1173771. | 215 |
| abstract_inverted_index.technique. | 181 |
| abstract_inverted_index.Determining | 31 |
| abstract_inverted_index.attenuation | 142 |
| abstract_inverted_index.endothelial | 190 |
| abstract_inverted_index.feasibility | 235 |
| abstract_inverted_index.genetically | 67 |
| abstract_inverted_index.haplotypes. | 248 |
| abstract_inverted_index.illustrates | 233 |
| abstract_inverted_index.integrated, | 251 |
| abstract_inverted_index.investigate | 259 |
| abstract_inverted_index.orthologous | 118 |
| abstract_inverted_index.pluripotent | 82 |
| abstract_inverted_index.population. | 30 |
| abstract_inverted_index.(natriuretic | 156 |
| abstract_inverted_index.ascertaining | 237 |
| abstract_inverted_index.challenging. | 53 |
| abstract_inverted_index.conformation | 89 |
| abstract_inverted_index.hypertension | 144 |
| abstract_inverted_index.interactions | 225 |
| abstract_inverted_index.particularly | 43 |
| abstract_inverted_index.salt-induced | 131 |
| abstract_inverted_index.upregulation | 150 |
| abstract_inverted_index.Additionally, | 216 |
| abstract_inverted_index.physiological | 33, 64, 239 |
| abstract_inverted_index.polymorphisms | 111 |
| abstract_inverted_index.recapitulated | 210 |
| abstract_inverted_index.reconstituted | 172 |
| abstract_inverted_index.significantly | 222 |
| abstract_inverted_index.vasodilation. | 163 |
| abstract_inverted_index.phenotypically | 70 |
| abstract_inverted_index.salt-sensitive | 127 |
| abstract_inverted_index.pressure-elevating | 166, 184, 219 |
| cited_by_percentile_year.max | 98 |
| cited_by_percentile_year.min | 91 |
| corresponding_author_ids | https://openalex.org/A5081888342, https://openalex.org/A5031428652 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 17 |
| corresponding_institution_ids | https://openalex.org/I138006243, https://openalex.org/I204308271 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.5400000214576721 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.86921097 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |