小柯机器人

近日，芬兰赫尔辛基大学Lauri A. Aaltonen、Eevi Kaasinen等研究人员合作发现，H2A.Z置入的不足与子宫肌瘤的发生有关。这一研究成果于2021年8月4日在线发表在国际学术期刊《自然》上。

研究人员创建了全基因组数据集，通过使用DNA、RNA、转座酶可及染色质检测（ATAC）、染色质免疫沉淀（ChIP）和HiC染色质免疫沉淀（HiChIP）对原始组织进行测序，研究人员揭示了子宫肌瘤（UL）的成因。研究人员确定了编码SRCAP组蛋白装载复合物六个成员基因的体细胞突变，并发现SRCAP成员YEATS4和ZNHIT1的生殖系突变使妇女容易患UL。在UL中，H2A.Z的占据率与染色质可及性和基因表达呈正相关，与DNA甲基化呈负相关，但在带有SRCAP复合体突变的肿瘤中这些相关性较弱。在这些肿瘤中，在H2A.Z丢失的转录起始位点出现了开放的染色质，这与基因的上调有关。此外，YEATS4的缺陷与二价胚胎干细胞基因的异常上调有关，正如以前在小鼠中显示的那样。

这项工作描述了一种潜在的肿瘤发生机制：由H2A.Z置入不足引起的表观遗传不稳定，并表明UL是通过染色质紊乱驱动的异常分化程序产生的，该程序由少数相互排斥的驱动突变产生。

据介绍，在绝经前的某个阶段，每四位女性中就有一位患有UL（子宫壁的良性肿瘤）。UL可导致过度出血、疼痛和不孕，并且是子宫切除的一个常见原因。它们的出现至少有三种不同的遗传因素：MED12或FH的突变，或HMGA23的基因组重排。

附：英文原文

Title: Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma

Author: Berta, Davide G., Kuisma, Heli, Vlimki, Niko, Risnen, Maritta, Jntti, Maija, Pasanen, Annukka, Karhu, Auli, Kaukomaa, Jaana, Taira, Aurora, Cajuso, Tatiana, Nieminen, Sanna, Penttinen, Rosa-Maria, Ahonen, Saija, Lehtonen, Rainer, Mehine, Miika, Vahteristo, Pia, Jalkanen, Jyrki, Sahu, Biswajyoti, Ravantti, Janne, Mkinen, Netta, Rajamki, Kristiina, Palin, Kimmo, Taipale, Jussi, Heikinheimo, Oskari, Btzow, Ralf, Kaasinen, Eevi, Aaltonen, Lauri A.

Issue&Volume: 2021-08-04

Abstract: One in four women suffers from uterine leiomyomas (ULs)—benign tumours of the uterine wall, also known as uterine fibroids—at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility1, and are a common cause of hysterectomy2. They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA23. Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex4, and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice5. Our work describes a potential mechanism of tumorigenesis—epigenetic instability caused by deficient H2A.Z deposition—and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.

DOI: 10.1038/s41586-021-03747-1

Source: https://www.nature.com/articles/s41586-021-03747-1

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