LncRNA 顺式与反式调控基因表达的差异分析

欧阳建志; OUYANG Jianzhi; 肖嘉怡; XIAO Jiayi; 陈祝彬; CHEN Zhubin; 廖萧雨; LIAO Xiaoyu; 黄丽芳; HUANG Lifang

doi:10.48014/jcss.20250125001

LncRNA 顺式与反式调控基因表达的差异分析

Differential Analysis of Cis-and Trans-Regulation of Gene Expression by LncRNA

中国统计科学学报 2025年第3卷第1期页码[26-38] 下载全文[4.1MB]

摘要

研究表明长链非编码RNA (lncRNA) 在多个层面上参与重要生命过程的调控。然而迄今为止, lncRNA调控基因表达的机制复杂性及其生物学功能尚未完全阐明。本论文主要针对lncRNA通过顺式和反式两种方式调控基因表达的差异及其动态行为开展研究: 一、基于化学主方程建立lncRNA功能作用的数学模型并验证明了SSA和FSP算法的准确性; 二、利用SSA和FSP算法分析lncRNA分布及转录爆发对基因表达的影响。本文结合动力系统理论和随机模拟方法, 首先构建基于实验结果的lncRNA调控机制模型; 然后通过计算模型的一些关键指标 (如mRNA的概率分布、均值和噪声等) , 分析lncRNA在顺式与反式调控中表现出的动态特性。研究表明原始模型下的反式调控的mRNA表达量更高且噪声更低, 而顺式调控对快速局部响应更加敏感, 还研究了lncRNA生成分布对mRNA表达的动态特性的影响, 发现不同分布形式显著影响调控模式的稳定性和表达效率。同时加入转录爆发后, 相比反式调控, 顺式调控mRNA的表达平均量更高且噪声更低。本研究为全面理解lncRNA的调控机制及其在基因表达中的功能特性提供了理论支持, 为探索lncRNA调控机制提供了新视角。

Abstract

Research has shown that long non-coding RNAs (lncRNAs) are involved in the regulation of essential biological processes at multiple levels. However so far, the mechanisms of gene expression regulation by lncRNAs and their biological functions are not yet fully understood. This study focuses on the differences in gene expression regulation by lncRNAs through cis-and trans-regulation and their dynamic behaviors. First, a mathematical model for the functional action of lncRNAs is established based on chemical master equations, and the accuracy of the SSA and FSP algorithms is validated. Second, the distribution of lncRNAs and the effect of transcriptional bursts on gene expression are analyzed using SSA and FSP algorithms. This paper combines dynamical system theory and stochastic simulation methods to first construct the model of lncRNA regulatory mechanisms based on experimental results; Then some key indicators ( such as the probability distribution, mean, and noise of mRNA) are then calculated to analyze the dynamic properties exhibited by lncRNAs in cis-and trans-regulation. The study shows that under the original model, trans-regulation leads to higher mRNA expression levels and lower noise, while cis-regulation is more sensitive to rapid local responses. The impact of the lncRNA generation distribution on the dynamic characteristics of mRNA expression is also studied, and it is found that different distribution forms significantly affect the stability and efficiency of the regulatory pattern. After adding transcriptional bursts, cisregulation results in higher average mRNA expression levels and lower noise compared to trans-regulation. This study provides theoretical support for a comprehensive understanding of lncRNA regulatory mechanisms and their functional characteristics in gene expression, offering a new perspective for exploring lncRNA regulatory mechanisms.

DOI	10.48014/jcss.20250125001
文章类型	研究性论文
收稿日期	2025-01-25
接收日期	2025-02-10
出版日期	2025-03-28
关键词	lncRNA, 顺式调控, 反式调控, 转录爆发
Keywords	lncRNA, Cis-regulation, Trans-regulation, transcription burst
作者	欧阳建志, 肖嘉怡, 陈祝彬, 廖萧雨, 黄丽芳^*
Author	OUYANG Jianzhi, XIAO Jiayi, CHEN Zhubin, LIAO Xiaoyu, HUANG Lifang^*
所在单位	广东财经大学统计与数学学院, 广州 510320
Company	School of Statistics and Mathematics, Guangdong University of Finance & Economics, Guangzhou 510320, China
浏览量	76
下载量	22
参考文献	[1] Mercer T R, Dinger M E, Mattick J S. Long non-coding RNAs: insights into functions[J]. Nat. Rev. Genet. , 2009, 10(3): 155-159. https://doi.org/10.1038/nrg2521 [2] Brockdorff N, Bowness J S, Wei G. Progress toward understanding chromosome silencing by Xist RNA[J]. Genes & development, 2020, 34(11-12): 733-744. https://doi.org/10.1101/gad.337196.120 [3] Senmatsu S, Hirota K. Roles of lncRNA transcription as a novel regulator of chromosomal function[J]. Genes & genetic systems, 2020, 95(5): 213-223. https://doi.org/10.1266/ggs.20-00024 [4] Tan Y T, Lin J F, Li T, et al. LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer[J]. Cancer Communications, 2021, 41(2): 109-120. https://doi.org/10.1002/cac2.12108 [5] Ferrer J, Dimitrova N. Transcription regulation by long non-coding RNAs: mechanisms and disease relevance[J]. Nature Reviews Molecular Cell Biology, 2024, 25(5): 396-415. https://doi.org/10.1038/s41580-023-00694-9 [6] Engreitz J M, Haines J E, Perez E M, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing[J]. Nature, 2016, 539(7629): 452-455. https://doi.org/10.1038/nature20149 [7] Johnsson P, Ziegenhain C, Hartmanis L, et al. Transcriptional kinetics and molecular functions of long noncoding RNAs[J]. Nature Genetics, 2022, 54(3): 306-317. https://doi.org/10.1038/s41588-022-01014-1 [8] Grossi E, Raimondi I, Goñi E, et al. A lncRNA-SWI/ SNF complex crosstalk controls transcriptional activation at specific promoter regions[J]. Nature Communications, 2020, 11(1): 936. https://doi.org/1038/s41467-020-14623-3 [9] Gao F, Cai Y, Kapranov P, et al. Reverse-genetics studies of lncRNAs—what we have learnt and paths forward[J]. Genome biology, 2020, 21: 1-23, https://doi.org/10.1186/s13059-020-01994-5 [10] Ørom U A, Shiekhattar R. Long noncoding RNAs usher in a new era in the biology of enhancers[J]. Cell, 2013, 154(6): 1190-1193. https://doi.org/10.1016/j.cell.2013.08.028 [11] Melé M, Rinn J L. “Cat’s Cradling” the 3D genome by the act of LncRNA transcription[J]. Molecular Cell, 2016, 62(5): 657-664. https://doi.org/10.1016/j.molcel.2016.05.011 [12] Amicone L, Marchetti A, Cicchini C. The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity[J]. Journal of Experimental & Clinical Cancer Research, 2023, 42(1): 147. https://doi.org/10.1186/s13046-023-02725-x [13] Siciliano V, Garzilli I, Fracassi C, et al. MiRNAs confer phenotypic robustness to gene networks by suppressing biological noise[J]. Nature communications, 2013, 4(1): 2364. https://doi.org/10.1038/ncomms3364 [14] Martirosyan A, Figliuzzi M, Marinari E, et al. Probing the limits to microRNA-mediated control of gene expression[J]. PLoS computational biology, 2016, 12(1): e1004715. https://doi.org/10.1371/journal.pcbi.1004715 [15] Grima R, Esmenjaud P M. Quantifying and correcting bias in transcriptional parameter inference from singlecell data[J]. Biophysical Journal, 2024, 123(1): 4-30. https://doi.org/10.1016/j.bpj.2023.10.021 [16] Warne D J, Baker R E, Simpson M J. Simulation and inference algorithms for stochastic biochemical reaction networks: from basic concepts to state-of-the-art[J]. Journal of the Royal Society Interface, 2019, 16(151): 20180943. https://doi.org/10.1098/rsif.2018.0943 [17] Jiao F, Li J, Liu T, et al. What can we learn when fitting a simple telegraph model to a complex gene expression model?[J]. PLOS Computational Biology, 2024, 20(5): e1012118. https://doi.org/10.1371/journal.pcbi.1012118 [18] Chen L, Zhu C, Jiao F. A generalized moment-based method for estimating parameters of stochastic gene transcription[J]. Mathematical Biosciences, 2022, 345: 108780. https://doi.org/10.1016/j.mbs.2022.108780 [19] Mattick, Amaral, Carninci. Long non-coding RNAs: definitions, functions, challenges and recommendations[J]. Nature Reviews Molecular Cell Biology, 2023, 24(6): 430-447. https://doi.org/10.1038/s41580-022-00566-8 [20] Bridges M C, Daulagala A C, Kourtidis A. LNCcation: lncRNA localization and function[J]. Journal of Cell Biology, 2021, 220(2): e202009045. https://doi.org/10.1083/jcb.202009045 [21] Fang K, Huang W, Sun Y M, et al. Cis-acting lnc-eRNA SEELA directly binds histone H4 to promote histone recognition and leukemia progression[J]. Genome Biology, 2020, 21: 1-23. https://doi.org/10.1186/s13059-020-02186-x [22] Gil N, Ulitsky I. Regulation of gene expression by cisacting long non-coding RNAs[J]. Nature Reviews Genetics, 2020, 21(2): 102-117. https://doi.org/10.1038/s41576-019-0184-5 [23] Saleh R O, Al-Ouqaili M T S, Ali E, et al. lncRNA-microRNA axis in cancer drug resistance: particular focus on signaling pathways[J]. Medical Oncology, 2024, 41(2): 52. https://doi.org/10.1007/s12032-023-02263-8 [24] Hou T Y, Kraus W L. Spirits in the material world: enhancer RNAs in transcriptional regulation[J]. Trends in biochemical sciences, 2021, 46(2): 138-153. https://doi.org/10.1016/j.tibs.2020.08.007 [25] Gong C, Fan Y, Zhou X, et al. Comprehensive analysis of expression and prognostic value of GATAs in lung cancer[J]. Journal of Cancer, 2021, 12(13): 3862. https://doi.org/10.7150/jca.52623 [26] Zhou, Liang, Dan R Littman. Transcriptional Regulatory Networks in Th17 Cell Differentiation[J]. Current Opinion in Immunology, 2009, 21(2): 146-152. https://doi.org/10.1016/j.coi.2009.03.001 [27] Tunnacliffe, Edward, Adam M. Corrigan, and Jonathan R. Chubb. Promoter-Mediated Diversification of Transcriptional Bursting Dynamics Following Gene Duplication[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(33): 8364-8369. https://doi.org/10.1073/pnas.1800943115 [28] Huang L, Yuan Z, Liu P, et al. Feedback-induced counterintuitive correlations of gene expression noise with bursting kinetics[J]. Physical Review E, 2014, 90(5): 052702. https://doi.org/10.1103/physreve.90.052702 [29] Liu T, Zhang J, Zhou T. Effect of interaction between chromatin loops on cell-to-cell variability in gene expression[J]. PLoS computational biology, 2016, 12(5): e1004917. https://doi.org/10.1371/journal.pcbi.1004917
引用本文	欧阳建志, 肖嘉怡, 陈祝彬, 等. LncRNA顺式与反式调控基因表达的差异分析[J]. 中国统计科学学报, 2025, 3(1): 26-38.
Citation	OUYANG Jianzhi, XIAO Jiayi, CHEN Zhubin, et al. Differential analysis of Cis-and Trans-Regulation of gene expression by LncRNA[J]. Journal of Chinese Statistical Sciences, 2025, 3(1): 26-38.