Dysregulation of Synaptic Signaling Genes Is Involved in Biology of Uterine Leiomyoma.

Jovan Krsteski,Maja Pakiž,Mario Gorenjak,Uroš Potočnik,Igor But

doi:10.3390/genes12081179

Jovan Krsteski, Maja Pakiž + Show 3 more

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https://doi.org/10.3390/genes12081179

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Journal: Genes	Publication Date: Jul 29, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: University Clinical Centre Maribor, University of Maribor

Abstract

Uterine leiomyomas are tumors, which are hormone driven and originate from the smooth muscle layer of the uterine wall. In addition to known genes in leiomyoma pathogenesis, recent approaches also highlight epigenetic malfunctions as an important mechanism of gene dysregulation. RNA sequencing raw data from pair-matched normal myometrium and fibroid tumors from two independent studies were used as discovery and validation sets and reanalyzed. RNA extracted from normal myometrium and fibroid tumors from 58 Slovenian patients was used as independent confirmation of most significant differentially expressed genes. Subsequently, GWA data from leiomyoma patients were used in order to identify genetic variants at epigenetic marks. Gene Ontology analysis of the overlap of two independent RNA-seq analyses showed that NPTX1, NPTX2, CHRM2, DRD2 and CACNA1A were listed as significant for several enriched GO terms. All five genes were subsequently confirmed in the independent Slovenian cohort. Additional integration and functional analysis showed that genetic variants in these five gene regions are listed at a chromatin structure and state, predicting promoters, enhancers, DNase hypersensitivity and altered transcription factor binding sites. We identified a unique subgroup of dysregulated synaptic signaling genes involved in the biology and pathogenesis of leiomyomas, adding to the complexity of tumor biology.

Highlights

Uterine leiomyomas (UL), known as uterine fibroids, are fibroid tumors that are hormone driven and originate from the smooth muscle layer of the uterine wall [1,2]
The discovery dataset was first filtered according to q value < 0.05 and loget > 2 or
The same RNAseq pipeline was applied to the validation cohort, where 443 significantly differentially expressed genes were observed in fibroid tumors relative to normal myometrium, using the same filtering thresholds (Table S1)

Summary

Introduction

Uterine leiomyomas (UL), known as uterine fibroids, are fibroid tumors that are hormone driven and originate from the smooth muscle layer of the uterine wall [1,2]. Recent work has revealed subtype-specific gene expression profiles, which supports the idea of different mechanisms of leiomyoma pathogenesis [11]. It was clearly shown that alterations in over-expression of TGF-β may contribute to the growth of UL [13,14]. Integration of transcriptomic and epigenetic changes has allowed for the identification of differential transcription factor occupancy, differential enhancer engagement consisting of histone acetylation, and altered enhancer–promoter contact rewiring as key events in UL gene dysregulation and differential expression [16]. Common loci between UL and other gynecological diseases or phenotypes have been identified by whole-genome association studies (GWAs) [18,19], implicating a complex background in the etiology of UL and insinuating the interplay of genetic variants and epigenetic expression regulation

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