美国宾夕法尼亚大学Jennifer E. Phillips-Cremins课题组揭示脆性X综合征中长突触基因的空间协调异染色质化。2023年12月21日，国际知名学术期刊《细胞》发表了这一成果。
研究人员表示，短串联重复（STR）的不稳定性会导致多种重复扩增疾病的转录沉默。在脆性X综合征（FXS）中，CGG STR的突变长度扩展通过局部DNA甲基化抑制FMR1。
研究人员发现在FXS患者衍生的iPSC、iPSC衍生的神经祖细胞、EBV转化的淋巴母细胞和突变长度CGG扩展的脑组织中，常染色体上存在兆碱基规模的H3K9me3域，并包含X染色体上的FMR1。H3K9me3域通过染色体间的相互作用连接起来，并划定了TAD和环的严重折叠错误。它们含有在S期末期复制的长突触基因、复制应激诱导的双链断裂，以及易发生逐步体细胞不稳定性的STR。
通过CRISPR工程化将突变长度的CGG改为突变前长度，可逆转X染色体和多个常染色体上的H3K9me3，重新折叠TAD，并恢复基因表达。在与基因组不稳定性相关的扰动下产生的正常长度iPSC中也会出现H3K9me3域，这表明其相关性超出了FXS。这些研究结果揭示了Mb级异染色质化以及易受不稳定性影响的基因位点之间的反式相互作用。
附：英文原文
Title: Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome
Author: Thomas Malachowski, Keerthivasan Raanin Chandradoss, Ravi Boya, Linda Zhou, Ashley L. Cook, Chuanbin Su, Kenneth Pham, Spencer A. Haws, Ji Hun Kim, Han-Seul Ryu, Chunmin Ge, Jennifer M. Luppino, Son C. Nguyen, Katelyn R. Titus, Wanfeng Gong, Owen Wallace, Eric F. Joyce, Hao Wu, Luis Alejandro Rojas, Jennifer E. Phillips-Cremins
Issue&Volume: 2023/12/21
Abstract: Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
DOI: 10.1016/j.cell.2023.11.019
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01273-4