Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA.
Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2023 Oct 30;14(1):6928. doi: 10.1038/s41467-023-42560-4.
The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
在早期胰腺发育过程中活跃的遗传调控变异对成年胰腺疾病和特征的影响尚不清楚。在这里，我们从全基因组测序个体中生成了 107 个人类诱导多能干细胞衍生的胰腺祖细胞（iPSC-PPC）的细胞系，并鉴定了 4065 个基因和 4016 个异构体，它们的表达和/或选择性剪接受到调控变异的影响。我们整合了在成人胰岛和整个胰腺样本中鉴定的 eQTL，揭示了 1805 个仅在类胎儿 iPSC-PPC 中特有的 eQTL 关联和 1043 个在类胎儿和成人胰腺组织中表现出调控可塑性的 eQTL。与胰腺疾病和特征的 GWAS 风险位点的共定位表明，一些假定的因果调节变体仅在类胎儿 iPSC-PPC 中活跃，并且可能通过调节疾病相关基因在早期发育中的表达来影响疾病，而其他具有调控可塑性的变体可能通过调节两个发育阶段中不同疾病基因的表达在胎儿和成人胰腺中发挥作用。
