Mathematical model of RNA-directed DNA methylation predicts tuning of negative feedback required for stable maintenance.

IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Open Biology Pub Date : 2024-11-01 Epub Date: 2024-11-13 DOI:10.1098/rsob.240159
Renee Dale, Rebecca Mosher
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Abstract

RNA-directed DNA methylation (RdDM) is a plant-specific de novo methylation pathway that is responsible for maintenance of asymmetric methylation (CHH, H = A, T or G) in euchromatin. Loci with CHH methylation produce 24 nucleotide (nt) short interfering (si) RNAs. These siRNAs direct additional CHH methylation to the locus, maintaining methylation states through DNA replication. To understand the necessary conditions to produce stable methylation, we developed a stochastic mathematical model of RdDM. The model describes DNA target search by siRNAs derived from CHH methylated loci bound by an Argonaute. Methylation reinforcement occurs either throughout the cell cycle (steady) or immediately following replication (bursty). We compare initial and final methylation distributions to determine simulation conditions that produce stable methylation. We apply this method to the low CHH methylation case. The resulting model predicts that siRNA production must be linearly proportional to methylation levels, that bursty reinforcement is more stable and that slightly higher levels of siRNA production are required for searching DNA, compared to RNA. Unlike CG methylation, which typically exhibits bi-modality with loci having either 100% or 0% methylation, CHH methylation exists across a range. Our model predicts that careful tuning of the negative feedback in the system is required to enable stable maintenance.

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RNA 引导的 DNA 甲基化数学模型预测了稳定维持所需的负反馈调整。
RNA 引导的 DNA 甲基化(RdDM)是一种植物特异的从头甲基化途径,负责维持外染色质中的不对称甲基化(CHH,H = A、T 或 G)。具有 CHH 甲基化的基因座会产生 24 个核苷酸(nt)的短干扰(si)RNA。这些 siRNA 将额外的 CHH 甲基化引导至基因座,通过 DNA 复制维持甲基化状态。为了了解产生稳定甲基化的必要条件,我们建立了一个 RdDM 随机数学模型。该模型描述了由 Argonaute 结合的来自 CHH 甲基化基因座的 siRNA 的 DNA 目标搜索。甲基化强化发生在整个细胞周期(稳定)或复制后立即发生(突发性)。我们比较了初始和最终甲基化分布,以确定产生稳定甲基化的模拟条件。我们将这种方法应用于低 CHH 甲基化情况。由此得出的模型预测,siRNA 的产生必须与甲基化水平成线性比例,突发性强化更为稳定,与 RNA 相比,搜索 DNA 所需的 siRNA 产生水平略高。CG 甲基化通常表现为双模式,即基因位点的甲基化程度要么为 100%,要么为 0%,而 CHH 甲基化则不同,存在一定的范围。我们的模型预测,需要对系统中的负反馈进行仔细调整,以实现稳定的维持。
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来源期刊
Open Biology
Open Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
10.00
自引率
1.70%
发文量
136
审稿时长
6-12 weeks
期刊介绍: Open Biology is an online journal that welcomes original, high impact research in cell and developmental biology, molecular and structural biology, biochemistry, neuroscience, immunology, microbiology and genetics.
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