Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
Department of Computer Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
Epigenetics Chromatin. 2024 May 6;17(1):13. doi: 10.1186/s13072-024-00528-8.
Multiple studies have demonstrated a negative correlation between gene expression and positioning of genes at the nuclear envelope (NE) lined by nuclear lamina, but the exact relationship remains unclear, especially in light of the highly stochastic, transient nature of the gene association with the NE.
In this paper, we ask whether there is a causal, systematic, genome-wide relationship between the expression levels of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei and the probabilities of TADs to be found at the NE. To investigate the nature of this possible relationship, we combine a coarse-grained dynamic model of the entire Drosophila nucleus with genome-wide gene expression data; we analyze the TAD averaged transcription levels of genes against the probabilities of individual TADs to be in contact with the NE in the control and lamins-depleted nuclei. Our findings demonstrate that, within the statistical error margin, the stochastic positioning of Drosophila melanogaster TADs at the NE does not, by itself, systematically affect the mean level of gene expression in these TADs, while the expected negative correlation is confirmed. The correlation is weak and disappears completely for TADs not containing lamina-associated domains (LADs) or TADs containing LADs, considered separately. Verifiable hypotheses regarding the underlying mechanism for the presence of the correlation without causality are discussed. These include the possibility that the epigenetic marks and affinity to the NE of a TAD are determined by various non-mutually exclusive mechanisms and remain relatively stable during interphase.
At the level of TADs, the probability of chromatin being in contact with the nuclear envelope has no systematic, causal effect on the transcription level in Drosophila. The conclusion is reached by combining model-derived time-evolution of TAD locations within the nucleus with their experimental gene expression levels.
多项研究表明，基因表达与核被膜（NE）上核纤层排列的基因位置之间存在负相关，但确切的关系仍不清楚，尤其是考虑到基因与 NE 结合的高度随机、瞬时性质。
在本文中，我们想知道果蝇核拓扑关联域（TAD）中基因表达水平与 TAD 存在于 NE 的概率之间是否存在全基因组范围内的因果关系。为了研究这种可能的关系，我们将整个果蝇核的粗粒度动态模型与全基因组基因表达数据相结合；我们分析了 TAD 中基因的平均转录水平与在对照和 lamin 耗尽核中单个 TAD 与 NE 接触的概率之间的关系。我们的发现表明，在统计误差范围内，果蝇 TAD 在 NE 中的随机定位本身并不会系统地影响这些 TAD 中的基因表达平均水平，而预期的负相关得到了证实。对于不包含核纤层相关结构域（LAD）的 TAD 或单独考虑的包含 LAD 的 TAD，这种相关性较弱，并且完全消失。讨论了没有因果关系的相关性的潜在机制的可验证假设。这些假设包括 TAD 的表观遗传标记和与 NE 的亲和力可能由各种非互斥机制决定，并在有丝分裂期间保持相对稳定。
在 TAD 水平上，染色质与核膜接触的概率对果蝇的转录水平没有系统的因果影响。这一结论是通过将模型推导的 TAD 在核内的时间演化与它们的实验基因表达水平相结合得出的。
