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

Davide G. Berta, Heli Kuisma, Niko Välimäki, Maritta Räisänen, Maija Jäntti, Annukka Pasanen, Auli Karhu, Jaana Kaukomaa, Aurora Taira, Tatiana Cajuso, Sanna Nieminen, Rosa-Maria Penttinen, Saija Ahonen, Rainer Lehtonen, Miika Mehine, Pia Vahteristo, Jyrki Jalkanen, Biswajyoti Sahu, Janne Ravantti, Netta Mäkinen, Kristiina Rajamäki, Kimmo Palin, Jussi Taipale, Oskari Heikinheimo, Ralf Bützow, Eevi Kaasinen () and Lauri A. Aaltonen ()
Additional contact information
Davide G. Berta: University of Helsinki
Heli Kuisma: University of Helsinki
Niko Välimäki: University of Helsinki
Maritta Räisänen: University of Helsinki
Maija Jäntti: University of Helsinki
Annukka Pasanen: University of Helsinki and Helsinki University Hospital
Auli Karhu: University of Helsinki
Jaana Kaukomaa: University of Helsinki
Aurora Taira: University of Helsinki
Tatiana Cajuso: University of Helsinki
Sanna Nieminen: University of Helsinki
Rosa-Maria Penttinen: University of Helsinki
Saija Ahonen: University of Helsinki
Rainer Lehtonen: University of Helsinki
Miika Mehine: University of Helsinki
Pia Vahteristo: University of Helsinki
Jyrki Jalkanen: Central Finland Central Hospital
Biswajyoti Sahu: University of Helsinki
Janne Ravantti: University of Helsinki
Netta Mäkinen: University of Helsinki
Kristiina Rajamäki: University of Helsinki
Kimmo Palin: University of Helsinki
Jussi Taipale: University of Helsinki
Oskari Heikinheimo: University of Helsinki and Helsinki University Hospital
Ralf Bützow: University of Helsinki
Eevi Kaasinen: University of Helsinki
Lauri A. Aaltonen: University of Helsinki

Nature, 2021, vol. 596, issue 7872, 398-403

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03747-1

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