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新方法实现对白血病染色质异质性的自动分析
作者:小柯机器人 发布时间:2021/10/23 20:10:26

美国霍华德休斯医学研究所Steven Henikoff团队近日取得一项新成果。经过不懈努力,他们揭示了混合谱系白血病染色质异质性的自动CUT&Tag分析。相关论文于2021年10月18日发表在《自然-遗传学》杂志上。

研究人员在基因组范围内探究了细胞系和患者样本中不同KMT2A肿瘤融合蛋白的融合特异性靶标。通过修改CUT&Tag染色质分析以实现完全自动化,研究人员揭示了由KMT2A肿瘤融合蛋白诱导的异常染色质导致的常见和肿瘤亚型特异性位点。KMT2A肿瘤融合结合位点的一个子集由二价(H3K4me3 和 H3K27me3)染色质特征标记,单细胞CUT&Tag分析显示这些位点具有细胞间异质性,这暗示了谱系可塑性。

此外,研究还发现基因体中H3K4me3的异常富集对Menin抑制剂敏感,证明了自动化染色质分析在识别治疗漏洞方面的效用。因此,自动化和单细胞CUT&Tag的结合可以揭示患者样本的表观基因组异质性并预测对治疗药物的敏感性。

据介绍,急性髓系和淋巴系白血病通常具有KMT2A基因染色体易位的特点,KMT2A基因编码KMT2A赖氨酸甲基转移酶(也称为混合谱系白血病-1),并导致KMT2A与其他染色质调节蛋白产生融合突变。

附:英文原文

Title: Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia

Author: Janssens, Derek H., Meers, Michael P., Wu, Steven J., Babaeva, Ekaterina, Meshinchi, Soheil, Sarthy, Jay F., Ahmad, Kami, Henikoff, Steven

Issue&Volume: 2021-10-18

Abstract: Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation induced by KMT2A oncofusion proteins. A subset of KMT2A oncofusion-binding sites are marked by bivalent (H3K4me3 and H3K27me3) chromatin signatures, and single-cell CUT&Tag profiling reveals that these sites display cell-to-cell heterogeneity suggestive of lineage plasticity. In addition, we find that aberrant enrichment of H3K4me3 in gene bodies is sensitive to Menin inhibitors, demonstrating the utility of automated chromatin profiling for identifying therapeutic vulnerabilities. Thus, integration of automated and single-cell CUT&Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents.

DOI: 10.1038/s41588-021-00941-9

Source: https://www.nature.com/articles/s41588-021-00941-9

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex