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Aberrations in the regulatory genome play a pivotal role in population-level disease predisposition. Annotation of the regulatory regions using appropriate primary tissues - instead of cell lines affected by selection and other confounding factors - could shed new light into mechanisms underlying common conditions. We test this approach in uterine leiomyomas, highly prevalent benign neoplasms of the myometrium, by creating 15-state chromatin annotations for myometrium and uterine leiomyomas. Integration with RNA-seq, ATAC-seq, HiChIP and methylation data enables us to compare the epigenomes of myometrium and ULs with distinct driver mutations, highlighting the role of bivalent regions in the neoplastic process. Subsequently, a genome wide association study meta-analysis is performed, using three different cohorts. Disease association loci are enriched at active chromatin, especially at enhancers, and harbor tumor- and driver mutation-specific chromatin states. At SATB2 locus we show the effect of the risk genotype already in the normal tissue. Integration of genome-wide association studies and deep regulatory genomics data from the correct tissue type represents a powerful approach in understanding population-level disease predisposition. The chromatin state origins of uterine leiomyoma (UL) remain to be explored. Here, the authors integrate data from genome-wide association studies and deep regulatory genomics data from myometrium and the three UL subclasses to understand population-level disease predisposition at chromatin state level.

The cohesin complex, which is essential for sister chromatid cohesion and chromosome segregation, also inhibits resolution of sister chromatid intertwinings (SCIs) by the topoisomerase Top2. The cohesin-related Smc5/6 complex (Smc5/6) instead accumulates on chromosomes after Top2 inactivation, known to lead to a buildup of unresolved SCIs. This suggests that cohesin can influence the chromosomal association of Smc5/6 via its role in SCI protection. Using high-resolution ChIP-sequencing, we show that the localization of budding yeast Smc5/6 to duplicated chromosomes indeed depends on sister chromatid cohesion in wild-type and top2-4 cells. Smc5/6 is found to be enriched at cohesin binding sites in the centromere-proximal regions in both cell types, but also along chromosome arms when replication has occurred under Top2-inhibiting conditions. Reactivation of Top2 after replication causes Smc5/6 to dissociate from chromosome arms, supporting the assumption that Smc5/6 associates with a Top2 substrate. It is also demonstrated that the amount of Smc5/6 on chromosomes positively correlates with the level of missegregation in top2-4, and that Smc5/6 promotes segregation of short chromosomes in the mutant. Altogether, this shows that the chromosomal localization of Smc5/6 predicts the presence of the chromatid segregation-inhibiting entities which accumulate in top2-4 mutated cells. These are most likely SCIs, and our results thus indicate that, at least when Top2 is inhibited, Smc5/6 facilitates their resolution.

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 infertility 1 , and are a common cause of hysterectomy 2 . They emerge through at least three distinct genetic drivers: mutations in MED12 or FH , or genomic rearrangement of HMGA2 3 . 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 complex 4 , 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 mice 5 . 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. Analyses of samples from 728 women with uterine leiomyomas (uterine fibroids), and public data, show that somatic and germline mutations in the SRCAP histone-loading complex genes are associated with the condition.

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis. Somatic heterozygous TET2 loss drives clonal hematopoiesis, which is linked to malignant cell degeneration and potentially cardiovascular disease. Here, the authors investigate the molecular impact of a germline TET2 mutation in a lymphoma family, finding elevated blood DNA methylation levels and no predisposition to atherosclerosis

The cohesin complex, which is essential for sister chromatid cohesion and chromosome segregation, also inhibits resolution of sister chromatid intertwinings (SCIs) by the topoisomerase Top2. The cohesin-related Smc5/6 complex (Smc5/6) instead accumulates on chromosomes after Top2 inactivation, known to lead to a buildup of unresolved SCIs. This suggests that cohesin can influence the chromosomal association of Smc5/6 via its role in SCI protection. Using high-resolution ChIP-sequencing, we show that the localization of budding yeast Smc5/6 to duplicated chromosomes indeed depends on sister chromatid cohesion in wild-type and top2-4 cells. Smc5/6 is found to be enriched at cohesin binding sites in the centromere-proximal regions in both cell types, but also along chromosome arms when replication has occurred under Top2-inhibiting conditions. Reactivation of Top2 after replication causes Smc5/6 to dissociate from chromosome arms, supporting the assumption that Smc5/6 associates with a Top2 substrate. It is also demonstrated that the amount of Smc5/6 on chromosomes positively correlates with the level of missegregation in top2-4, and that Smc5/6 promotes segregation of short chromosomes in the mutant. Altogether, this shows that the chromosomal localization of Smc5/6 predicts the presence of the chromatid segregation-inhibiting entities which accumulate in top2-4 mutated cells. These are most likely SCIs, and our results thus indicate that, at least when Top2 is inhibited, Smc5/6 facilitates their resolution.

Monitoring Essential Ocean, Climate, and Biodiversity Variables (EOVs, ECVs and EBVs) collected through the marine Research Infrastructures (RIs) is critical for assessing environmental status, improving scientific knowledge and defining environmental policies. This study evaluates the capacity of the Italian marine monitoring system, including facilities such as fixed stations, buoys, autonomous platforms, and mobile systems across the Mediterranean Sea, to produce those variables. Conducted in 2023 within the framework of the ITINERIS project ( https://itineris.cnr.it/ ), which aims to strengthen coordination among national and ESFRI RIs (European Strategy Forum on Research Infrastructures), the analysis systematically examines the spatial, thematic, and technological coverage of EOVs, ECVs, EBVs observations and their alignment with international standards for environmental monitoring of 155 facilities from eight Italian and pan-European marine RIs. Of the 107 EVs recognized, 50% were actively produced by the RIs considered, with over 90% meeting the established requirements for EVs. These numbers will be updated to reflect the new equipment acquired during the project’s implementation up to early 2026, which is expected to boost EVs production by approximately 38-40%. The national monitoring network demonstrates a high degree of maturity for oceanic and climate variables, while biodiversity observations remain less represented, indicating the need for further technological innovation and automation. These findings emphasize the importance of enhancing coordination and harmonization among RIs to ensure balanced and interoperable monitoring. The study provides key recommendations to strengthen Italy’s capacity to contribute to the global characterization of EOVs, ECVs, and EBVs and to support evidence-based environmental assessments and the development of robust environmental management strategies at European level.

In December 2022, members of the Convention on Biological Diversity adopted the new Kunming-Montreal Global Biodiversity Framework (GBF) (https://www.cbd.int/gbf/targets/) to guide international biodiversity conservation efforts until 2030 in order to be able to live ‘in harmony with nature’ by 2050. This framework addresses the implementation gap left after the Aichi Biodiversity Targets, which were the previous global instrument for mainstreaming biodiversity conservation between 2010 and 2020 (IPBES, Díaz et al. Citation2019). As biodiversity continues to decline (IPBES, Díaz et al. Citation2019), the global scholarly community has been integrally involved in the development of the GBF, advancing crucial insights to support biodiversity strategies and action plans at different scales over time to ensure fair and effective conservation. In addition, the current situation demands that greater attention is paid to the diverse forms of human-nature connectedness and the co-production of knowledge and solutions by academia, governments, private sectors, alongside local communities and Indigenous Peoples to tackle issues of equity in biodiversity conservation, research, and management (Wyborn et al. Citation2021). Further research into the underlying political and justice dimensions of conservation and the recognition and inclusion of diverse knowledge systems and their holders (Pascual et al. Citation2022) is needed to support the actual achievement of the new Global Biodiversity Targets (for 2030) and Goals (for 2050).

A 2-year dataset of a stand-alone mooring, deployed in November 2020 down the Levante Canyon in the eastern Ligurian Sea, is presented. The Levante Canyon Mooring (LCM) is a deep submarine multidisciplinary observatory positioned at 608 m depth in a key ecosystem area. The Levante Canyon hosts a valuable and vulnerable ecosystem of deep-living cold-water corals (CWCs), studied and monitored since 2013 through integrated mapping of the seabed and water column. The 2-year dataset, acquired on the mooring and presented here (data from November 2020 to October 2022), includes measurements conducted with both current meters and conductivity–temperature–depth (CTD) probes and provides information about the hydrodynamics and thermohaline properties across almost the entire water column. The observatory is still ongoing, and the dataset is regularly updated. All the described data are publicly available from https://doi.org/10.17882/92236 (Borghini et al., 2022). They must therefore be preserved and are of considerable scientific interest.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.