Understanding How Chromatin Folding and Enzyme Competition Affect Rugged Epigenetic Landscapes.

IF 2 4区 数学 Q2 BIOLOGY
Daria Stepanova, Meritxell Brunet Guasch, Helen M Byrne, Tomás Alarcón
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引用次数: 0

Abstract

Epigenetics plays a key role in cellular differentiation and maintaining cell identity, enabling cells to regulate their genetic activity without altering the DNA sequence. Epigenetic regulation occurs within the context of hierarchically folded chromatin, yet the interplay between the dynamics of epigenetic modifications and chromatin architecture remains poorly understood. In addition, it remains unclear what mechanisms drive the formation of rugged epigenetic patterns, characterised by alternating genomic regions enriched in activating and repressive marks. In this study, we focus on post-translational modifications of histone H3 tails, particularly H3K27me3, H3K4me3, and H3K27ac. We introduce a mesoscopic stochastic model that incorporates chromatin architecture and competition of histone-modifying enzymes into the dynamics of epigenetic modifications in small genomic loci comprising several nucleosomes. Our approach enables us to investigate the mechanisms by which epigenetic patterns form on larger scales of chromatin organisation, such as loops and domains. Through bifurcation analysis and stochastic simulations, we demonstrate that the model can reproduce uniform chromatin states (open, closed, and bivalent) and generate previously unexplored rugged profiles. Our results suggest that enzyme competition and chromatin conformations with high-frequency interactions between distant genomic loci can drive the emergence of rugged epigenetic landscapes. Additionally, we hypothesise that bivalent chromatin can act as an intermediate state, facilitating transitions between uniform and rugged landscapes. This work offers a powerful mathematical framework for understanding the dynamic interactions between chromatin architecture and epigenetic regulation, providing new insights into the formation of complex epigenetic patterns.

了解染色质折叠和酶竞争如何影响崎岖的表观遗传景观
表观遗传学在细胞分化和维持细胞身份中起着关键作用,使细胞能够在不改变DNA序列的情况下调节其遗传活性。表观遗传调控发生在分层折叠染色质的背景下,然而表观遗传修饰的动力学和染色质结构之间的相互作用仍然知之甚少。此外,目前尚不清楚是什么机制驱动了粗糙的表观遗传模式的形成,其特征是富含激活和抑制标记的交替基因组区域。在本研究中,我们重点关注组蛋白H3尾部的翻译后修饰,特别是H3K27me3、H3K4me3和H3K27ac。我们引入了一个介观随机模型,该模型将染色质结构和组蛋白修饰酶的竞争纳入由几个核小体组成的小基因组位点的表观遗传修饰动力学中。我们的方法使我们能够研究表观遗传模式在染色质组织(如环和结构域)的更大尺度上形成的机制。通过分岔分析和随机模拟,我们证明该模型可以再现均匀的染色质状态(开放、封闭和二价),并生成以前未探索的崎岖剖面。我们的研究结果表明,酶竞争和染色质构象与远距离基因组位点之间的高频相互作用可以驱动崎岖表观遗传景观的出现。此外,我们假设二价染色质可以作为一种中间状态,促进均匀和崎岖景观之间的过渡。这项工作为理解染色质结构和表观遗传调控之间的动态相互作用提供了一个强大的数学框架,为复杂表观遗传模式的形成提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.90
自引率
8.60%
发文量
123
审稿时长
7.5 months
期刊介绍: The Bulletin of Mathematical Biology, the official journal of the Society for Mathematical Biology, disseminates original research findings and other information relevant to the interface of biology and the mathematical sciences. Contributions should have relevance to both fields. In order to accommodate the broad scope of new developments, the journal accepts a variety of contributions, including: Original research articles focused on new biological insights gained with the help of tools from the mathematical sciences or new mathematical tools and methods with demonstrated applicability to biological investigations Research in mathematical biology education Reviews Commentaries Perspectives, and contributions that discuss issues important to the profession All contributions are peer-reviewed.
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