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Multi-omic QTL Analysis in Pancreatic Progenitor Cells Reveal Early Developmental Insights into Adult Obesity and Diabetes Risk
Multi-omic QTL Analysis in Pancreatic Progenitor Cells Reveal Early Developmental Insights into Adult Obesity and Diabetes Risk
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151255
- ISBN
- 9798384087458
- DDC
- 574
- 서명/저자
- Multi-omic QTL Analysis in Pancreatic Progenitor Cells Reveal Early Developmental Insights into Adult Obesity and Diabetes Risk
- 발행사항
- [Sl] : University of California, San Diego, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 145 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: Frazer, Kelly A.;Ohno-Machado, Lucila.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Diego, 2024.
- 초록/해제
- 요약Adverse events during fetal pancreas development can result in insulin resistance, impaired glucose metabolism, and loss of beta cell function, leading to an increased risk of developing diabetes in adulthood. While current quantitative trait loci (QTL) datasets have been instrumental in characterizing genetic variants associated with diabetes, they only reflect molecular associations present in mature adult tissues. Furthermore, only a fraction of diabetes-associated loci colocalize with QTLs identified in adult whole pancreas and islet tissues. Given the important role of fetal development in adult diabetes predisposition, interrogating the molecular effects of genetic variation during this crucial period could provide valuable mechanistic insights into the etiology of obesity and diabetes. First, we conducted an eQTL analysis on 107 RNA-seq samples from iPSC-derived pancreatic progenitor cells (PPC) to map genetic loci associated with gene expression and isoform usage changes during early pancreas development. Colocalization with eQTLs from adult pancreatic tissues identified genetic variants that were either specifically active during early pancreas development, specifically active in the adult pancreatic stage, or shared across both stages but had stage-unique regulatory functions. Colocalization with genome-wide association studies (GWAS) loci revealed developmental-unique eQTLs with potential roles in glucose homeostasis or diabetes, including those associated with TPD52, CDC37L1-DT, MEG3, and CDH3. Second, we conducted chromatin accessibility QTL (caQTL) analysis using matched PPC ATAC-seq samples. We found that caQTL variants were enriched in distal regulatory regions, including CTCF-binding sites and PPC-specific super enhancer regions, and were enriched for motifs of transcription factors expressed in pancreatic progenitors. Colocalization of eQTLs, caQTLs, and GWAS signals identified putative regulatory mechanisms for TPD52 expression and its impact on fasting glucose levels, as well as KIT and its impact on body mass index. Together, this body of work provides a unique and powerful resource for interrogating the molecular effects of genetic variation during early pancreas development and their potential impact on adult complex pancreatic traits and disease.
- 일반주제명
- Bioinformatics
- 일반주제명
- Genetics
- 일반주제명
- Developmental biology
- 기타저자
- University of California, San Diego Bioinformatics and Systems Biology
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151255
■006m o d
■007cr#unu||||||||
■020 ▼a9798384087458
■035 ▼a(MiAaPQ)AAI30992913
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aNguyen, Jennifer Phuong.
■24510▼aMulti-omic QTL Analysis in Pancreatic Progenitor Cells Reveal Early Developmental Insights into Adult Obesity and Diabetes Risk
■260 ▼a[Sl]▼bUniversity of California, San Diego▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a145 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: Frazer, Kelly A.;Ohno-Machado, Lucila.
■5021 ▼aThesis (Ph.D.)--University of California, San Diego, 2024.
■520 ▼aAdverse events during fetal pancreas development can result in insulin resistance, impaired glucose metabolism, and loss of beta cell function, leading to an increased risk of developing diabetes in adulthood. While current quantitative trait loci (QTL) datasets have been instrumental in characterizing genetic variants associated with diabetes, they only reflect molecular associations present in mature adult tissues. Furthermore, only a fraction of diabetes-associated loci colocalize with QTLs identified in adult whole pancreas and islet tissues. Given the important role of fetal development in adult diabetes predisposition, interrogating the molecular effects of genetic variation during this crucial period could provide valuable mechanistic insights into the etiology of obesity and diabetes. First, we conducted an eQTL analysis on 107 RNA-seq samples from iPSC-derived pancreatic progenitor cells (PPC) to map genetic loci associated with gene expression and isoform usage changes during early pancreas development. Colocalization with eQTLs from adult pancreatic tissues identified genetic variants that were either specifically active during early pancreas development, specifically active in the adult pancreatic stage, or shared across both stages but had stage-unique regulatory functions. Colocalization with genome-wide association studies (GWAS) loci revealed developmental-unique eQTLs with potential roles in glucose homeostasis or diabetes, including those associated with TPD52, CDC37L1-DT, MEG3, and CDH3. Second, we conducted chromatin accessibility QTL (caQTL) analysis using matched PPC ATAC-seq samples. We found that caQTL variants were enriched in distal regulatory regions, including CTCF-binding sites and PPC-specific super enhancer regions, and were enriched for motifs of transcription factors expressed in pancreatic progenitors. Colocalization of eQTLs, caQTLs, and GWAS signals identified putative regulatory mechanisms for TPD52 expression and its impact on fasting glucose levels, as well as KIT and its impact on body mass index. Together, this body of work provides a unique and powerful resource for interrogating the molecular effects of genetic variation during early pancreas development and their potential impact on adult complex pancreatic traits and disease.
■590 ▼aSchool code: 0033.
■650 4▼aBioinformatics
■650 4▼aGenetics
■650 4▼aDevelopmental biology
■653 ▼aInsulin resistance
■653 ▼aQuantitative trait loci
■653 ▼aPancreatic progenitor cells
■653 ▼aGenome-wide association studies
■690 ▼a0715
■690 ▼a0369
■690 ▼a0758
■71020▼aUniversity of California, San Diego▼bBioinformatics and Systems Biology.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0033
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161083▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
