Species-specific chromatin structure and its environmental interaction in craniofacial skeletal development andvariation using cichlid fishes

慈鲷的物种特异性染色质结构及其在颅面骨骼发育和变异中的环境相互作用

• 批准号: 10046780
• 负责人: Kara E Powder
• 金额: $ 44.45万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046780
• 关键词: ATAC-seq; Address; Adult; Animals; Bioinformatics; Biological Assay; Bromodomain; Chemicals; Chromatin; Chromatin Structure; Chromatin Structure Alteration; Cichlids; Clinical; Clinical Treatment; Clinical Trials; Code; Congenital Abnormality; Consequentialism; Craniofacial Abnormalities; DNA; DNA Packaging; Development; Disease; Drug Prescriptions; Environment; Epigenetic Process; Exposure to; Face; Feeding behaviors; Fellowship; Financial Hardship; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; Grant; Heart Diseases; Histone Acetylation; Histone Deacetylase; Histones; Human; Immersion; Investigation; Knowledge; Lead; Link; Malignant Neoplasms; Molecular; Morphology; Mouse Strains; Mutation; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phenotype; Post-Translational Protein Processing; Pregnant Women; Production; Proteins; Radiation; Reader; Research; Research Personnel; Risk; Risk Factors; Role; Schedule; Series; Skeletal Development; Skeleton; Source; Structure; Teratogenic effects; Teratogens; Time; Transposase; Variant; Vertebrates; Work; base; congenital anomaly; craniofacial; epigenetic regulation; epigenetic variation; gene environment interaction; histone modification; innovation; insight; malformation; novel; programs; response; shape analysis; skeletal; small molecule; transcriptome sequencing; undergraduate student

PROJECT SUMMARY Variation in the craniofacial skeleton produces both a spectrum of unique faces and as well as clinical malformations. Congenital craniofacial anomalies are one of the most common birth defects. In addition to genetic changes, we are increasingly recognizing the importance of the physical packaging of DNA in the regulation of gene expression and development, and the resulting genotype-phenotype relationship. A major determinant of this epigenetic regulation is post-translational modifications of histone proteins, which alters the structure of chromatin and access to DNA. The goal of this work is to determine how variation in chromatin structure, in particular histone acetylation, impacts phenotypic variation of the facial skeleton. We will capitalize on the unparalleled natural craniofacial variation among the evolutionary radiation of non-model cichlid fishes. Given that cichlid facial variation mimics human facial variation and the molecular control of facial development is conserved across vertebrates, this may yield novel insights into the epigenetic basis of variation in human faces. In Aim 1, we will comprehensively quantify variation in chromatin structure and DNA accessibility using ATAC-seq (Assay for Transposase Accessible Chromatin) and the downstream transcriptional effects using RNA-seq. These genomic analyses will be conducted in three cichlid species with diverse adult morphologies at three developmental time points key for facial divergence. In Aim 2, we will use pharmacological agents to alter the activity of proteins associated with histone acetylation during distinct windows of facial development. We will focus on four drugs that are potential sources of birth defects in humans; these drugs are in clinical trials for treatment of diseases from cancer to heart disease, but the FDA does not currently note a potential risk for pregnant women. Completion of this aim will determine windows of sensitivity for epigenetic changes and potential teratogenic effects of these drugs. Applying these drugs in closely-related cichlids (comparable to comparing different mouse strains), allows investigation of gene by environment (GxE) interactions previously demonstrated for similar drugs. This work will address a major gap in our knowledge of the genotype- phenotype relationship, the role of epigenetic regulation in phenotypic variation. Application of drugs to cichlid fishes enables discovery of genetic interactions that may define sensitivity to exposure and risk of craniofacial malformations in humans. In line with the goals of the R15 AREA grant, undergraduates will conduct bioinformatic analyses in Aim 1, and lead pharmacological manipulations in Aim 2. Grant funds will support four new undergraduate researchers, including summer fellowships that enable a full immersion in research without the constraints of a full class schedule.

项目总结

项目成果

Morphometric and Genetic Description of Trophic Adaptations in Cichlid Fishes.

• DOI: 10.3390/biology11081165
• 发表时间: 2022-08-03
• 期刊: Biology
• 影响因子: 4.2

Genetic basis of ecologically relevant body shape variation among four genera of cichlid fishes.

慈鲷四个属生态相关体形变异的遗传基础。

• DOI: 10.1111/mec.16977
• 发表时间: 2023
• 期刊: Molecular ecology
• 影响因子: 4.9
• 作者: DeLorenzo,Leah;Mathews,Destiny;Brandon,AAllyson;Joglekar,Mansi;CarmonaBaez,Aldo;Moore,EmilyC;Ciccotto,PatrickJ;Roberts,NatalieB;Roberts,ReadeB;Powder,KaraE
• 通讯作者: Powder,KaraE

Neural crest cells as a source of microevolutionary variation.

• DOI: 10.1016/j.semcdb.2022.06.001
• 发表时间: 2023-08
• 期刊: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
• 影响因子: 7.3
• 作者: Brandon, A. Allyson;Almeida, Daniela;Powder, Kara E.
• 通讯作者: Powder, Kara E.