Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans.

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-04-10 DOI:10.1016/j.xgen.2024.100536
Tyler J Hansen, Sarah L Fong, Jessica K Day, John A Capra, Emily Hodges
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Abstract

Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using assay for transposase-accessible chromatin coupled to self-transcribing active regulatory region (ATAC-STARR) sequencing. In addition to thousands of cis changes, we discover an unexpected number (∼10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie ∼37% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans, revealing a substantial role for trans divergence-alone and together with cis changes-in regulatory differences between species.

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人类基因调控进化的动力来自顺式和反式调控元件功能的分化。
物种间的基因调控差异可能来自调控元件 DNA 序列顺式作用的局部变化,也可能来自调控环境的全局性反式作用变化。对这些机制如何驱动调控进化的理解一直受到识别跨作用变化的挑战的限制。我们提出了一种综合方法,利用转座酶可接触染色质与自转录活性调控区(ATAC-STARR)测序相结合的检测方法,直接鉴定人类和猕猴淋巴母细胞之间的顺式和反式差异调控元件。除了数以千计的顺式变化外,我们还发现了意想不到的反式变化数量(∼10,000),并表明顺式和反式元件表现出不同的序列差异和功能模式。我们进一步确定了导致37%反式差异的不同表达的转录因子,并追踪顺式变化如何产生级联反式变化。总之,我们发现大多数差异元素(67%)都经历了顺式和反式的变化,揭示了反式差异--单独或与顺式变化一起--在物种间调控差异中的重要作用。
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