Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats
Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats
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宫内生长迟缓大鼠胰岛转录因子结合及基因二价的改变
DOI：
10.3390/cells9061435
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发表时间：
2020-06-01
期刊：
影响因子：
6
通讯作者：
Simmons, Rebecca A.
中科院分区：
文献类型：
--
作者：
Lien, Yu-Chin;Wang, Paul Zhiping;Simmons, Rebecca A.
宫内生长迟缓（IUGR），诱导表观遗传修饰和基因表达的永久性变化，已与2型糖尿病的发展。使用IUGR大鼠模型，我们进行了ChIP-Seq，以识别和定位2周和10周大鼠胰岛中的全基因组组组蛋白修饰和基因失调。IUGR诱导2周和10周胰岛中H3 K4 me 3、H3 K27 me 3和H3 K27 Ac标记物的富集发生显著变化，这与IUGR胰岛中对胰岛功能至关重要的多个基因的表达变化相关。ChIP-Seq分析显示IUGR诱导的组蛋白标记变化富集在关键的转录因子结合基序上，如C/EBP、Ets 1、Bcl 6、Thrb、Ebf 1、Sox 9和Mitf。这些转录因子在我们先前发表的转录组研究中也被鉴定为上游调控因子。此外，我们的ChIP-seq数据揭示了超过1000个潜在的二价基因，如通过富集H3 K4 me 3和H3 K27 me 3所鉴定的。IUGR改变了许多潜在的二价基因的平衡状态，特别是关键的胰岛基因Acod 1、Fgf 21、Serpina 11、Cdh 16、Lrrc 27和Lrrc 66。总的来说，我们的研究结果表明，组蛋白修饰的关键转录因子和基因，可能有助于长期基因失调和异常胰岛表型IUGR大鼠的改变。
Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularlyAcod1, Fgf21, Serpina11, Cdh16, Lrrc27,andLrrc66,key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.