Single-cell epigenomic phenotyping of IMPC-generated mouse lines lacking chromatin regulators

项目概要/摘要 表观遗传机制对哺乳动物的发育至关重要，该机制的组成部分是 在多种人类疾病中发生突变。数以百计的调节蛋白参与阅读，写， 在生物体的生命周期中消除表观遗传信息。然而，这些化合物中的许多的体内活性是不稳定的。 表观遗传调节因子的特征仍然不充分。在这里，我们利用IMPC生成的小鼠品系 缺乏表观遗传调节因子，以及单细胞表观基因组学和转录组学的最新进展， 技术，在分子水平上询问体内表观遗传机制的组成部分， 细胞类型的分辨率，了解他们在发展和疾病的复杂作用。产生的数据 本研究将揭示多种组织中由于表观遗传调节因子丢失而导致的基因调节缺陷， 与人类先天性畸形相关的细胞类型。这种组织和细胞类型分辨的观点， 表观遗传机制的突变是揭示表观遗传机制的更大努力的关键一步， 影响疾病风险，解释非编码序列变异，并最终定制诊断和 本发明涉及用于治疗患者的致病细胞的表观基因组和转录组状态的药物。

Project Summary/Abstract The epigenetic machinery is essential for mammalian development, and components of this machinery are mutated in a variety of human diseases. Hundreds of regulatory proteins participate in the reading, writing, and erasing of epigenetic information over the lifespan of an organism. However, the in vivo activity of many of these epigenetic regulators remain inadequately characterized. Here, we leverage IMPC-generated mouse lines lacking epigenetic regulators, together with recent advances in single-cell epigenomic and transcriptomic technologies, to interrogate components of the epigenetic machinery in vivo at the molecular level, and with the cell-type resolution necessary to understand their complex roles in development and disease. The data produced here will reveal gene regulatory defects caused by loss of epigenetic regulators in a diverse panel of tissues and cell types relevant to human congenital malformations. This tissue- and cell-type-resolved view of the effects of mutations in the epigenetic machinery is a critical step in larger efforts to reveal mechanisms of epigenetically- influenced disease risk, interpret non-coding sequence variation, and ultimately to tailor diagnostics and therapeutics to the epigenomic and transcriptomic states of a patient’s disease-contributing cells.