PDF(Pubmed)
Abstract：
Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.
摘要：
人胰腺的发育需要通过表观遗传机制和关键转录因子的结合对基因表达进行精确的时间控制。我们定量了受孕后6至21周的供体的人胎儿胰腺样品中DNA甲基化的全基因组模式。我们发现整个胰腺发育过程中DNA甲基化发生了戏剧性的变化，超过21％的位点被表征为发育差异甲基化位置（dDMP），包括许多注释与单基因糖尿病相关的基因。对出生后胰腺组织中DNA甲基化的分析表明，在发育中的胰腺中发生的DNA甲基化的急剧时间变化在很大程度上限于产前时期。在许多常染色体位点，男性和女性之间观察到DNA甲基化的显着差异，在整个胰腺发育过程中，一小部分位点显示出性别特异性DNA甲基化轨迹。胰腺dDMP在基因组中分布不均，并且在以开放染色质和已知胰腺发育转录因子结合为特征的调节域中被耗尽。最后,我们将我们的胰腺dDMPs与以前的人脑发现进行了比较，确定DNA甲基化中组织特异性发育变化的证据。这项研究代表了人类胎儿胰腺发育过程中DNA甲基化模式的首次系统探索，并证实了产前时期是主要的表观基因组可塑性时期。
