Venu Vrinda, Small Eric M, Roth Cullen, Adikari Samantha H, Vlot Anna Hendrika Cornelia, Sullivan Kyle A, Abeyratne Chanaka Roshan, Jacobson Daniel, Starkenburg Shawn R, Sanbonmatsu Karissa Y, Steadman Christina R
Genomics and Bioanalytics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
Climate, Ecology and Environment Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
Epigenetics Chromatin. 2025 Oct 3;18(1):63. doi: 10.1186/s13072-025-00631-4.
Epigenetic modifications, nucleosome occupancy, and three-dimensional chromatin architecture collectively create a multi-layered, highly interactive regulatory system for controlling genomic functionality. Dysregulation of epigenetic processes leads to a plethora of abnormalities including disease states. Therapies focused on epigenetic modulation can alter gene expression to correct dysfunction, though the perpetuation of these states and the relationships among chromatin regulatory layers is not well understood.
Here, we investigated global and local chromatin structural and functional responses after acute histone deacetylase inhibitor treatment (suberoylanilide hydroxamic acid) in lung cancer cells across time. Treatment substantially increased global histone acetylation resulting in a pervasive but not distinctive signature. The spread of acetylation did not significantly impact global chromatin accessibility, and nucleosome remodeling largely occurred at finer scales in functionally relevant genomic regions. Indeed, both H3K4 trimethylation, a mark of active transcription, and gene expression changes were altered in a controlled locus-specific manner, suggesting aberrant acetylation indirectly leads to balanced and bidirectional gene expression profiles from tighter regulation of other chromatin features. HDACi treatment induced (13%) genomic rearrangement in chromatin compartmentalization and moderate weakening of topologically associating domains.
Continuous wavelet analysis of these features demonstrates that scale-dependent, locus-specific factors influence the relationship between chromatin architecture and functional output, suggesting that regulation of transcription and nucleosome remodeling is not entirely (nor linearly) dependent upon large scale compartment exchange. Structural and functional responses are most pronounced early after treatment with partial persistence of differential local chromatin features and expression later in time; this highlights the plasticity of chromatin regulation, which may have implications for the efficacy of epigenetic treatments. These results demonstrate the effectiveness of multi-layered regulation of transcription: in resilient systems, disruption of one chromatin feature does not distort the regulation of other features in supporting a transcriptional program that allows for survival.
表观遗传修饰、核小体占据情况以及三维染色质结构共同构成了一个多层、高度交互式的调控系统，用于控制基因组功能。表观遗传过程的失调会导致包括疾病状态在内的大量异常情况。专注于表观遗传调控的疗法可以改变基因表达以纠正功能障碍，然而这些状态的持续存在以及染色质调控层之间的关系尚未得到充分理解。
在这里，我们研究了肺癌细胞在急性组蛋白去乙酰化酶抑制剂（辛二酰苯胺异羟肟酸）处理后不同时间的全局和局部染色质结构及功能反应。处理显著增加了全局组蛋白乙酰化，产生了一种普遍但不独特的特征。乙酰化的扩散并未显著影响全局染色质可及性，并且核小体重塑主要在功能相关基因组区域的更精细尺度上发生。实际上，活性转录标记H3K4三甲基化以及基因表达变化都以可控的位点特异性方式发生改变，这表明异常乙酰化通过对其他染色质特征的更严格调控间接导致平衡且双向的基因表达谱。HDACi处理诱导了染色质区室化中的（13%）基因组重排以及拓扑相关结构域的适度减弱。
对这些特征的连续小波分析表明，依赖尺度的、位点特异性因素影响染色质结构与功能输出之间的关系，这表明转录调控和核小体重塑并不完全（也不是线性地）依赖于大规模区室交换。结构和功能反应在处理后早期最为明显，不同局部染色质特征和表达在后期会部分持续；这突出了染色质调控的可塑性，这可能对表观遗传治疗的疗效产生影响。这些结果证明了转录多层调控的有效性：在弹性系统中，一种染色质特征的破坏不会扭曲其他特征在支持允许生存的转录程序中的调控。
