小柯机器人

近日，美国斯坦福大学医学院Paul A. Khavari等研究人员合作绘制出表皮分化的动态组合顺式调控词典。这一研究成果于2021年10月14日在线发表在国际学术期刊《自然—遗传学》上。

研究人员表示，转录因子与顺式调控元件（CRE）中的DNA序列模体词汇结合，在细胞状态转换期间调节染色质状态和基因表达。由于顺式调控编码的组合性质，对模体词汇如何影响动态调控活动的定量理解一直难以实现。

为了解决这个问题，研究人员对整个表皮分化过程中的染色质和表达动态进行了多组学数据分析，以确定与3609个动态表达基因相关的40103个动态CRE，然后应用一个可解释的深度学习框架来模拟染色质可及性的顺式调控逻辑。这个分析框架确定了动态CRE中合作的DNA序列规则，并调节在皮肤分化中具有不同作用的同步基因模块。大规模并行报告试验分析验证了时间动态和合作性顺式调控逻辑。与人类多基因皮肤病有关的变体富集在这些随时间变化的组合模体规则中。这种综合方法显示了表皮分化的组合式顺式调控词典，并且是破译动态基因调控下顺式调控编码组织原则的通用框架。

附：英文原文

Title: The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation

Author: Kim, Daniel S., Risca, Viviana I., Reynolds, David L., Chappell, James, Rubin, Adam J., Jung, Namyoung, Donohue, Laura K. H., Lopez-Pajares, Vanessa, Kathiria, Arwa, Shi, Minyi, Zhao, Zhixin, Deep, Harsh, Sharmin, Mahfuza, Rao, Deepti, Lin, Shin, Chang, Howard Y., Snyder, Michael P., Greenleaf, William J., Kundaje, Anshul, Khavari, Paul A.

Issue&Volume: 2021-10-14

Abstract: Transcription factors bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we undertook multiomic data profiling of chromatin and expression dynamics across epidermal differentiation to identify 40,103 dynamic CREs associated with 3,609 dynamically expressed genes, then applied an interpretable deep-learning framework to model the cis-regulatory logic of chromatin accessibility. This analysis framework identified cooperative DNA sequence rules in dynamic CREs regulating synchronous gene modules with diverse roles in skin differentiation. Massively parallel reporter assay analysis validated temporal dynamics and cooperative cis-regulatory logic. Variants linked to human polygenic skin disease were enriched in these time-dependent combinatorial motif rules. This integrative approach shows the combinatorial cis-regulatory lexicon of epidermal differentiation and represents a general framework for deciphering the organizational principles of the cis-regulatory code of dynamic gene regulation. A deep-learning framework interprets multiomic data across epidermal differentiation, identifying cooperative DNA sequence rules that regulate gene modules. Massively parallel reporter assay analysis validates temporal dynamics and cis-regulatory logic.

DOI: 10.1038/s41588-021-00947-3

Source: https://www.nature.com/articles/s41588-021-00947-3

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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