意大利圣拉斐尔科学研究所Giovanni Tonon、Davide Cittaro等研究人员合作通过异染色质和常染色质的单细胞分析揭示表观遗传动态。相关论文于2021年10月11日在线发表在《自然—生物技术》杂志上。

研究人员设计了一种包括异染色质蛋白-1α（HP-1α）克罗莫结构域（CD）的混合转座酶，它通过与组蛋白3上赖氨酸9的三甲基化（H3K9me3）的结合参与异染色质的组装和维持，并开发了一种单细胞方法。单细胞基因组和表观基因组转座酶测序（scGET-seq），与单细胞转座酶可及染色质的测序（scATAC-seq）不同，它全面探测开放和封闭的染色质，并同时记录基因组序列。研究人员在癌细胞类器官和人源异种移植（PDX）模型中测试了scGET-seq，并确定了导致癌症耐药性的遗传事件和可塑性驱动机制。

接下来，在封闭和开放染色质的不同富集基础上，研究人员设计了一种方法，即"Chromatin Velocity"，来确定单细胞水平上的表观遗传修饰轨迹。Chromatin Velocity发现了干细胞重编程过程中的表观遗传重组路径，并确定了驱动这些发育过程的关键转录因子。scGET-seq揭示了任何细胞过程中的基因组和表观遗传景观的动态。

据悉，最近的研究已经成功地在单细胞水平上调查了开放染色质，但对异染色质及其基本基因组决定因素的高通量、单细胞评估仍然具有挑战性。

附：英文原文

Title: Chromatin Velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin

Author: Tedesco, Martina, Giannese, Francesca, Lazarevi, Dejan, Giansanti, Valentina, Rosano, Dalia, Monzani, Silvia, Catalano, Irene, Grassi, Elena, Zanella, Eugenia R., Botrugno, Oronza A., Morelli, Leonardo, Panina Bordignon, Paola, Caravagna, Giulio, Bertotti, Andrea, Martino, Gianvito, Aldrighetti, Luca, Pasqualato, Sebastiano, Trusolino, Livio, Cittaro, Davide, Tonon, Giovanni

Issue&Volume: 2021-10-11

Abstract: Recent efforts have succeeded in surveying open chromatin at the single-cell level, but high-throughput, single-cell assessment of heterochromatin and its underlying genomic determinants remains challenging. We engineered a hybrid transposase including the chromodomain (CD) of the heterochromatin protein-1α (HP-1α), which is involved in heterochromatin assembly and maintenance through its binding to trimethylation of the lysine 9 on histone 3 (H3K9me3), and developed a single-cell method, single-cell genome and epigenome by transposases sequencing (scGET-seq), that, unlike single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), comprehensively probes both open and closed chromatin and concomitantly records the underlying genomic sequences. We tested scGET-seq in cancer-derived organoids and human-derived xenograft (PDX) models and identified genetic events and plasticity-driven mechanisms contributing to cancer drug resistance. Next, building upon the differential enrichment of closed and open chromatin, we devised a method, Chromatin Velocity, that identifies the trajectories of epigenetic modifications at the single-cell level. Chromatin Velocity uncovered paths of epigenetic reorganization during stem cell reprogramming and identified key transcription factors driving these developmental processes. scGET-seq reveals the dynamics of genomic and epigenetic landscapes underlying any cellular processes.

DOI: 10.1038/s41587-021-01031-1

Source: https://www.nature.com/articles/s41587-021-01031-1