# A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding

## TL;DR

This study explores how genetic changes in uterine fibroids may cause heavy menstrual bleeding by affecting nearby womb lining tissues.

## Contribution

The study reveals that fibroid mutations influence endometrial RNA splicing, linking genetic changes to abnormal bleeding.

## Key findings

- MED12 mutations in fibroids correlate with altered RNA splicing in the endometrium.
- Variants in AHR and COL4A6 are identified as contributing to fibroid-related symptoms.
- Altered splicing in endometrium is linked to pathways involving angiogenesis and extracellular matrix.

## Abstract

Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood.

To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients.

In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding.

This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.

Uterine fibroids are common benign non-cancerous tumours that grow in the womb and affect many women, often causing pain, heavy menstrual bleeding and problems with fertility. Genes are made up of DNA and are inherited. They provide instructions for making proteins and RNA, other molecules within the body. It is known that certain genes are associated with people having fibroids, but how fibroids cause symptoms like heavy menstrual bleeding is still unclear. We examined fibroid and endometrial tissues from 91 women and looked at the DNA, protein and RNA present. We found changes in fibroid tissues and discovered that these changes may also affect nearby endometrial tissues, which line the womb. This can alter how genes and proteins are expressed and may explain why bleeding occurs. These findings provide new insight into how uterine fibroids affect the body and may help develop better treatments to manage symptoms and improve women’s health in the future.

Wang, Philpott et al. perform integrative genomic, transcriptomic and proteomic analyses across fibroid, myometrium, and endometrium tissues to uncover mechanisms underlying uterine fibroid (UF) associated heavy menstrual bleeding. Signalling from MED12-mutated fibroids alters RNA splicing events in the endometrium.