Portillo-Ledesma Stephanie, Hang Minna, Schlick Tamar
Department of Chemistry, New York University, 100 Washington Square East, Silver Building, New York, New York 10003, United States.
Simons Center for Computational Physical Chemistry, New York University, 24 Waverly Place, Silver Building, New York, New York 10003, United States.
Biochemistry. 2025 May 6;64(9):2100-2115. doi: 10.1021/acs.biochem.5c00029. Epub 2025 Apr 27.
Huntington's disease (HD) is a neurological condition caused by an excessive expansion of CAG repeats in the Huntingtin (HTT) gene. Although experiments have shown an altered epigenetic landscape and chromatin architecture upon HD development, the structural consequences on the HTT gene remain elusive. Structural data are only available for model nucleosome systems and yeast systems with human nucleosomes. Here, we use our experimentally validated nucleosome-resolution mesoscale chromatin model to investigate folding changes of the HTT gene associated with HD. We investigate how the histone fold domain of the variant macroH2A1, a biomarker of HD, affects the genome structure by modeling HD-like systems that contain (i) 100% canonical, (ii) 100% macroH2A1, (iii) 50% canonical and 50% macroH2A1, and (iv) 100% hybrid cores (one canonical H2A and one macroH2A1 per nucleosome). Then, we model the mouse HTT gene in healthy and HD conditions by incorporating the CAG expansion and macroH2A1 cores, reducing the linker histone density and tail acetylation levels, and incorporating genomic contacts. Overall, our results show that the histone fold domain of macroH2A1 affects chromatin compaction in a fiber-dependent manner (i.e., nucleosome distribution dependent) and can thus both enhance or repress HTT gene expression. Our modeling of the HTT gene shows that HTT is less compact in the diseased condition, which could accelerate the production of the mutated protein. By suggesting the structural biophysical consequences of the HTT gene under HD conditions, our findings may help in the development of diagnostic and therapeutic treatments for HD.
亨廷顿舞蹈病（HD）是一种由亨廷顿蛋白（HTT）基因中CAG重复序列过度扩增引起的神经疾病。尽管实验表明HD发生时表观遗传格局和染色质结构发生了改变，但HTT基因的结构后果仍不清楚。结构数据仅适用于模型核小体系统和含有人核小体的酵母系统。在此，我们使用经过实验验证的核小体分辨率中尺度染色质模型来研究与HD相关的HTT基因折叠变化。我们通过对包含（i）100%标准型、（ii）100%macroH2A1型、（iii）50%标准型和50%macroH2A1型以及（iv）100%杂交核心（每个核小体一个标准型H2A和一个macroH2A1）的HD样系统进行建模，研究HD生物标志物变体macroH2A1的组蛋白折叠结构域如何影响基因组结构。然后，我们通过纳入CAG扩增和macroH2A1核心、降低连接组蛋白密度和尾部乙酰化水平以及纳入基因组接触，对健康和HD条件下的小鼠HTT基因进行建模。总体而言，我们的结果表明，macroH2A1的组蛋白折叠结构域以纤维依赖性方式（即核小体分布依赖性）影响染色质压缩，因此既可以增强也可以抑制HTT基因表达。我们对HTT基因的建模表明，在患病状态下HTT的压缩程度较低，这可能会加速突变蛋白的产生。通过揭示HD条件下HTT基因的结构生物物理后果，我们的发现可能有助于HD诊断和治疗方法的开发。
