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Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma
Nature ( IF 50.5 ) Pub Date : 2021-08-04 , DOI: 10.1038/s41586-021-03747-1
Davide G Berta 1, 2 , Heli Kuisma 1, 2 , Niko Välimäki 1, 2 , Maritta Räisänen 1, 2 , Maija Jäntti 1, 2 , Annukka Pasanen 3 , Auli Karhu 1, 2 , Jaana Kaukomaa 1, 2 , Aurora Taira 1, 2 , Tatiana Cajuso 1, 2 , Sanna Nieminen 1, 2 , Rosa-Maria Penttinen 1, 2 , Saija Ahonen 1, 2 , Rainer Lehtonen 1, 2 , Miika Mehine 1, 2 , Pia Vahteristo 1, 2 , Jyrki Jalkanen 4 , Biswajyoti Sahu 2 , Janne Ravantti 1, 2 , Netta Mäkinen 1, 2 , Kristiina Rajamäki 1, 2 , Kimmo Palin 1, 2, 5 , Jussi Taipale 2 , Oskari Heikinheimo 6 , Ralf Bützow 2, 3 , Eevi Kaasinen 1, 2 , Lauri A Aaltonen 1, 2, 5
Affiliation  

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.



中文翻译:

H2A.Z 沉积不足与子宫平滑肌瘤的发生有关

四分之一的女性在绝经前的某个阶段患有子宫平滑肌瘤 (ULs)——子宫壁的良性肿瘤,也称为子宫肌瘤。UL 可导致过度出血、疼痛和不孕1,并且是子宫切除术的常见原因2。它们通过至少三种不同的遗传驱动因素出现:MED12FH突变,或HMGA2 3基因组重排. 在这里,我们创建了全基因组数据集,使用 DNA、RNA、转座酶可及染色质 (ATAC) 测定、染色质免疫沉淀 (ChIP) 和 HiC 染色质免疫沉淀 (HiChIP) 测序对原发组织进行深入了解 UL 的起源。我们在编码 SRCAP 组蛋白负载复合物4的六个成员的基因中发现了体细胞突变,并发现 SRCAP 成员YEATS4ZNHIT1中的种系突变使女性易患 UL。携带这些突变的肿瘤显示组蛋白变体 H2A.Z 的沉积缺陷。在 UL 中,H2A.Z 占有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,但这些相关性在携带 SRCAP 复杂突变的肿瘤中较弱。在这些肿瘤中,开放染色质出现在 H2A.Z 丢失的转录起始位点,这与基因的上调有关。此外,YEATS4缺陷与二价胚胎干细胞基因的异常上调有关,如先前在小鼠中所示5. 我们的工作描述了肿瘤发生的潜在机制——由 H2A.Z 沉积不足引起的表观遗传不稳定性——并表明 UL 是通过由少量相互排斥的驱动突变引起的染色质紊乱驱动的异常分化程序产生的。

更新日期:2021-08-04
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