Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes
Human odontogenic aberrations such as abnormal tooth number and delayed tooth eruption can occur as a symptom of rare syndromes or, more commonly, as nonsyndromic phenotypes. These phenotypes can require extensive and expensive dental treatment, posing a significant burden. While many dental phenoty...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-11-01
|
| Series: | Frontiers in Dental Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fdmed.2022.1009264/full |
| _version_ | 1797986435097165824 |
|---|---|
| author | Emma Wentworth Winchester Alexis Hardy Justin Cotney Justin Cotney |
| author_facet | Emma Wentworth Winchester Alexis Hardy Justin Cotney Justin Cotney |
| author_sort | Emma Wentworth Winchester |
| collection | DOAJ |
| description | Human odontogenic aberrations such as abnormal tooth number and delayed tooth eruption can occur as a symptom of rare syndromes or, more commonly, as nonsyndromic phenotypes. These phenotypes can require extensive and expensive dental treatment, posing a significant burden. While many dental phenotypes are heritable, most nonsyndromic cases have not been linked to causal genes. We demonstrate the novel finding that common sequence variants associated with human odontogenic phenotypes are enriched in developmental craniofacial enhancers conserved between human and mouse. However, the bulk nature of these samples obscures if this finding is due to the tooth itself or the surrounding tissues. We therefore sought to identify enhancers specifically active in the tooth anlagen and quantify their contribution to the observed genetic enrichments. We systematically identified 22,001 conserved enhancers active in E13.5 mouse incisors using ChIP-seq and machine learning pipelines and demonstrated biologically relevant enrichments in putative target genes, transcription factor binding motifs, and in vivo activity. Multi-tissue comparisons of human and mouse enhancers revealed that these putative tooth enhancers had the strongest enrichment of odontogenic phenotype-associated variants, suggesting a role for dysregulation of tooth developmental enhancers in human dental phenotypes. The large number of these regions genome-wide necessitated prioritization of enhancer loci for future investigations. As enhancers modulate gene expression, we prioritized regions based on enhancers' putative target genes. We predicted these target genes and prioritized loci by integrating chromatin state, bulk gene expression and coexpression, GWAS variants, and cell type resolved gene expression to generate a prioritized list of putative odontogenic phenotype-driving loci active in the developing tooth. These genomic regions are of particular interest for downstream experiments determining the role of specific dental enhancer:gene pairs in odontogenesis. |
| first_indexed | 2024-04-11T07:33:46Z |
| format | Article |
| id | doaj.art-1c3c3bb3d8e4442da9a816fd056eb1de |
| institution | Directory Open Access Journal |
| issn | 2673-4915 |
| language | English |
| last_indexed | 2024-04-11T07:33:46Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Dental Medicine |
| spelling | doaj.art-1c3c3bb3d8e4442da9a816fd056eb1de2022-12-22T04:36:48ZengFrontiers Media S.A.Frontiers in Dental Medicine2673-49152022-11-01310.3389/fdmed.2022.10092641009264Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypesEmma Wentworth Winchester0Alexis Hardy1Justin Cotney2Justin Cotney3DMD/PhD Program, University of Connecticut School of Dental Medicine, Farmington, CT, United StatesMaster of Genetics Program, Paris Diderot University, Paris, FranceDepartment of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, United StatesInstitute for Systems Genomics, University of Connecticut, Storrs, CT, United StatesHuman odontogenic aberrations such as abnormal tooth number and delayed tooth eruption can occur as a symptom of rare syndromes or, more commonly, as nonsyndromic phenotypes. These phenotypes can require extensive and expensive dental treatment, posing a significant burden. While many dental phenotypes are heritable, most nonsyndromic cases have not been linked to causal genes. We demonstrate the novel finding that common sequence variants associated with human odontogenic phenotypes are enriched in developmental craniofacial enhancers conserved between human and mouse. However, the bulk nature of these samples obscures if this finding is due to the tooth itself or the surrounding tissues. We therefore sought to identify enhancers specifically active in the tooth anlagen and quantify their contribution to the observed genetic enrichments. We systematically identified 22,001 conserved enhancers active in E13.5 mouse incisors using ChIP-seq and machine learning pipelines and demonstrated biologically relevant enrichments in putative target genes, transcription factor binding motifs, and in vivo activity. Multi-tissue comparisons of human and mouse enhancers revealed that these putative tooth enhancers had the strongest enrichment of odontogenic phenotype-associated variants, suggesting a role for dysregulation of tooth developmental enhancers in human dental phenotypes. The large number of these regions genome-wide necessitated prioritization of enhancer loci for future investigations. As enhancers modulate gene expression, we prioritized regions based on enhancers' putative target genes. We predicted these target genes and prioritized loci by integrating chromatin state, bulk gene expression and coexpression, GWAS variants, and cell type resolved gene expression to generate a prioritized list of putative odontogenic phenotype-driving loci active in the developing tooth. These genomic regions are of particular interest for downstream experiments determining the role of specific dental enhancer:gene pairs in odontogenesis.https://www.frontiersin.org/articles/10.3389/fdmed.2022.1009264/fullodontogenesisgene regulation and expressionenhancer activationchromatin regulationsingle cell RNA analysismultiomic analysis |
| spellingShingle | Emma Wentworth Winchester Alexis Hardy Justin Cotney Justin Cotney Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes Frontiers in Dental Medicine odontogenesis gene regulation and expression enhancer activation chromatin regulation single cell RNA analysis multiomic analysis |
| title | Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes |
| title_full | Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes |
| title_fullStr | Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes |
| title_full_unstemmed | Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes |
| title_short | Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes |
| title_sort | integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes |
| topic | odontogenesis gene regulation and expression enhancer activation chromatin regulation single cell RNA analysis multiomic analysis |
| url | https://www.frontiersin.org/articles/10.3389/fdmed.2022.1009264/full |
| work_keys_str_mv | AT emmawentworthwinchester integrationofmultimodaldatainthedevelopingtoothrevealscandidateregulatorylocidrivinghumanodontogenicphenotypes AT alexishardy integrationofmultimodaldatainthedevelopingtoothrevealscandidateregulatorylocidrivinghumanodontogenicphenotypes AT justincotney integrationofmultimodaldatainthedevelopingtoothrevealscandidateregulatorylocidrivinghumanodontogenicphenotypes AT justincotney integrationofmultimodaldatainthedevelopingtoothrevealscandidateregulatorylocidrivinghumanodontogenicphenotypes |