Integrated transcriptomic and epigenomic analysis of primary human lung epithelial cell differentiation.
Integrated transcriptomic and epigenomic analysis of primary human lung epithelial cell differentiation.
复制标题
DOI：
10.1371/journal.pgen.1003513
复制
发表时间：
2013-06
期刊：
影响因子：
4.5
通讯作者：
Laird-Offringa IA
中科院分区：
文献类型：
--
作者：
Marconett CN;Zhou B;Rieger ME;Selamat SA;Dubourd M;Fang X;Lynch SK;Stueve TR;Siegmund KD;Berman BP;Borok Z;Laird-Offringa IA
阐明细胞类型特异性基因调控的表观遗传学基础是充分了解分化细胞的不同表型是如何实现和保持的关键。在这里，我们研究了表观遗传变化如何与转录激活相结合，以确定分化过程中的细胞表型。我们利用体外分化的人原代肺泡上皮细胞(AEC)进行了表观基因组图谱分析和转录图谱分析。该模型重述了AEC在肺损伤后再生过程中从一种分化细胞类型转变为另一种细胞类型的体内过程。随着时间的推移，对组蛋白标记的询问显示，在改变染色质结构的区域内，特定的转录因子结合基序丰富。这些基序与显示转录变化的途径的交叉参考揭示了已知的远端肺泡分化调控途径，如WNT和转化生长因子β(TGFb)途径，以及可能的成人AEC分化的新调节因子，包括肝细胞核因子4α(HNF4a)和维甲酸X受体(RXR)信号通路。抑制RXR通路证实了其与肺泡分化的功能相关性。我们加入了表观遗传学数据，从而能够特定地识别转录因子，这些转录因子是分化过程的潜在直接上游调节因子，展示了这种方法的力量。表观基因组数据与转录图谱的整合在识别其他分化模式中的调控途径方面有着广泛的应用。了解表观遗传控制基因表达的作用对于全面描述生物过程，如发育和再生至关重要。在这里，我们利用远端肺细胞的分化来深入了解表观遗传格局、分子信号事件以及最终转录和表型变化之间的相关性。我们发现，通过将表观遗传学特征与全基因组转录数据相结合，我们能够确定哪些分子信号事件在成人肺泡上皮细胞分化过程中被激活和抑制，并确定了导致这些变化的表观遗传学变化。此外，我们验证了这些预测的但先前未识别的通路之一，维甲酸X受体信号通路在这一过程中的作用。
Elucidation of the epigenetic basis for cell-type specific gene regulation is key to gaining a full understanding of how the distinct phenotypes of differentiated cells are achieved and maintained. Here we examined how epigenetic changes are integrated with transcriptional activation to determine cell phenotype during differentiation. We performed epigenomic profiling in conjunction with transcriptomic profiling using in vitro differentiation of human primary alveolar epithelial cells (AEC). This model recapitulates an in vivo process in which AEC transition from one differentiated cell type to another during regeneration following lung injury. Interrogation of histone marks over time revealed enrichment of specific transcription factor binding motifs within regions of changing chromatin structure. Cross-referencing of these motifs with pathways showing transcriptional changes revealed known regulatory pathways of distal alveolar differentiation, such as the WNT and transforming growth factor beta (TGFB) pathways, and putative novel regulators of adult AEC differentiation including hepatocyte nuclear factor 4 alpha (HNF4A), and the retinoid X receptor (RXR) signaling pathways. Inhibition of the RXR pathway confirmed its functional relevance for alveolar differentiation. Our incorporation of epigenetic data allowed specific identification of transcription factors that are potential direct upstream regulators of the differentiation process, demonstrating the power of this approach. Integration of epigenomic data with transcriptomic profiling has broad application for the identification of regulatory pathways in other models of differentiation. Understanding the role of epigenetic control of gene expression is critical to the full description of biological processes, such as development and regeneration. Herein we utilize the differentiation of cells from the distal lung to gain insight into the correlation between the epigenetic landscape, molecular signaling events, and eventual changes in transcription and phenotype. We found that by integrating epigenetic profiling with whole genome transcriptomic data we were able to determine which molecular signaling events were activated and repressed during adult alveolar epithelial cell differentiation, and we identified epigenetic changes that contributed to these changes. Furthermore, we validated the role of one of these predicted but not previously identified pathways, retinoid X receptor signaling, in this process.
登录
查看更多内容
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
24.3
作者：
Hind, M;Maden, M
通讯作者：
Maden, M
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
15.9
作者：
Chapman, Harold A.;Li, Xiaopeng;Vu, Thiennu H.
通讯作者：
Vu, Thiennu H.