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江南大学数学与数据科学学院,江苏 无锡 214122
Received:04 March 2026,
Revised:2026-04-23,
Online First:27 April 2026,
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赵凤语, 张硕霞, 王耀来. 转录因子的增强子搜寻机理[J]. 合成生物学, 2026, 7. DOI: 10.12211/2096-8280.2026-013
ZHAO Fengyu, ZHANG Shuoxia, WANG Yaolai. Molecular Mechanisms Governing Transcription Factor Search for Enhancers[J]. Synthetic Biology Journal, 2026, 7. DOI: 10.12211/2096-8280.2026-013
转录因子如何在细胞核中高效搜索并定位增强子,是个看似简单却困扰至今的经典难题。其内在机理的揭示,将为细胞信号转导设计提供不可或缺的理论基础。经典的自由扩散模型和易化扩散模型认为,转录因子在细胞核中自由扩散,可沿DNA滑动、跳跃,并可在不同的DNA链之间跳转。为解决此类模型固有的搜寻低效难题,导向搜索模型提议,细胞核内存在为转录因子提供导航的“路标”。然而,关于“路标”及“导航机制”的研究尚处于初级阶段,未知和困惑远多于已知。转录凝聚体和短串联重复序列的发现,为这一问题的解答提供了新思路。本文在综述现有模型的基础上,概括提出短串联重复序列与转录凝聚体通过“引导与富集—浓缩与催化”的互补机制共同保障转录因子在复杂染色质环境中实现快速而精准的靶点定位。该模型为理解增强子搜寻机理与相关DNA序列设计提供了新视角。
It remains elusive how transcription factors (TFs) efficiently search for and localize enhancers. Unraveling the dynamic mechanisms is not only fundamental to understanding gene regulation but also provides a critical theoretical framework for engineering cellular signal transduction pathways. Classical models
including free diffusion model and facilitated diffusion model
posit that TFs diffuse freely through the nucleoplasm
engage in non-specific DNA binding
and navigate the genome via sliding
hopping
or intersegmental transfer until encountering their cognate enhancers. While these theories are well-supported by experimental evidence in prokaryotes
they lack validation in eukaryotes and fail to recapitulate the physicochemical complexity of the eukaryotic nucleus
particularly densely packed chromatin environment. To address the inefficiency inherent to random diffusion
the guided exploration model has emerged
proposing that nuclear "signpost" elements
such as specific chromatin structures or protein assemblies
direct TF trafficking. However
research into the identity of these signposts and the underlying "navigation mechanisms" remains in its infancy
with fundamental questions far outnumbering definitive answers. In recent years
the discovery of transcriptional condensates and short tandem repeats (STRs) inspired new insights. TFs harboring intrinsically disordered regions (IDRs) can undergo liquid-liquid phase separation (LLPS) to form biomolecular condensates. These condensates functionally mimic nuclear signposts
serving as spatial beacons that guide TF search processes and
as supported by emerging evidence
potentiate gene transcriptional activation. Concurrently
STRs are enriched surrounding enhancers
where they directly interact with TFs and play pivotal roles in eukaryotic gene regulation. Here
we review the canonical TF search models
the LLPS-driven formation of transcriptional condensates
and the functional roles of STRs in enhancer biology. We propose an integrated model wherein STRs and transcriptional condensates act in synergy to enable rapid and precise TF targeting within complex chromatin. This complementary mechanism
termed "guidance and enrichment
concentration and catalysis"
resolves key inefficiencies of classical diffusion models and offers a conceptual framework for deciphering enhancer selection and engineering synthetic DNA regulatory sequences.
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