BACKGROUND Uterine leiomyomas, also known as uterine fibroids or myomas, are the most common benign gynecological tumors and are found in women of reproductive and postmenopausal age. There is an exceptionally high prevalence of this tumor in women by the age of 50 years. Black women are particularly affected, with an increased incidence, earlier age of onset, larger and faster growing fibroids and greater severity of symptoms as compared to White women. Although advances in identifying genetic and environmental factors to delineate these fibroids have already been made, only recently has the role of epigenomics in the pathogenesis of this disease been considered. OBJECTIVE AND RATIONALE Over recent years, studies have identified multiple epigenomic aberrations that may contribute to leiomyoma development and growth. This review will focus on the most recent discoveries in three categories of epigenomic changes found in uterine fibroids, namely aberrant DNA methylation, histone tail modifications and histone variant exchange, and their translation into altered target gene architecture and transcriptional outcome. The findings demonstrating how the altered 3D shape of the enhancer can regulate gene expression from millions of base pairs away will be discussed. Additionally, translational implications of these discoveries and potential roadblocks in leiomyoma treatment will be addressed. SEARCH METHODS A comprehensive PubMed search was performed to identify published articles containing keywords relevant to the focus of the review, such as: uterine leiomyoma, uterine fibroids, epigenetic alterations, epigenomics, stem cells, chromatin modifications, extracellular matrix [ECM] organization, DNA methylation, enhancer, histone post-translational modifications and dysregulated gene expression. Articles until September 2021 were explored and evaluated to identify relevant updates in the field. Most of the articles focused on in the discussion were published between 2015 and 2021, although some key discoveries made before 2015 were included for background information and foundational purposes. We apologize to the authors whose work was not included because of space restrictions or inadvertent omission. OUTCOMES Chemical alterations to the DNA structure and of nucleosomal histones, without changing the underlying DNA sequence, have now been implicated in the phenotypic manifestation of uterine leiomyomas. Genome-wide DNA methylation analysis has revealed subsets of either suppressed or overexpressed genes accompanied by aberrant promoter methylation. Furthermore, differential promoter access resulting from altered 3D chromatin structure and histone modifications plays a role in regulating transcription of key genes thought to be involved in leiomyoma etiology. The dysregulated genes function in tumor suppression, apoptosis, angiogenesis, ECM formation, a variety of cancer-related signaling pathways and stem cell differentiation. Aberrant DNA methylation or histone modification is also observed in altering enhancer architecture, which leads to changes in enhancer–promoter contact strength, producing novel explanations for the overexpression of high mobility group AT-hook 2 and gene dysregulation found in mediator complex subunit 12 mutant fibroids. While many molecular mechanisms and epigenomic features have been investigated, the basis for the racial disparity observed among those in the Black population remains unclear. WIDER IMPLICATIONS A comprehensive understanding of the exact pathogenesis of uterine leiomyoma is lacking and requires attention as it can provide clues for prevention and viable non-surgical treatment. These findings will widen our knowledge of the role epigenomics plays in the mechanisms related to uterine leiomyoma development and highlight novel approaches for the prevention and identification of epigenome targets for long-term non-invasive treatment options of this significantly common disease.

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子宫平滑肌瘤的表观基因组和增强子失调

背景技术子宫平滑肌瘤，也称为子宫肌瘤或肌瘤，是最常见的良性妇科肿瘤，见于育龄妇女和绝经后妇女。到 50 岁时，这种肿瘤在女性中的患病率特别高。黑人女性尤其受影响，与白人女性相比，发病率更高、发病年龄更早、肌瘤更大且生长更快，症状更严重。尽管在识别遗传和环境因素以描述这些肌瘤方面已经取得了进展，但直到最近才考虑表观基因组学在这种疾病的发病机制中的作用。目的和基本原理 近年来，研究已经确定了多种表观基因组畸变，这些畸变可能有助于平滑肌瘤的发展和生长。本综述将重点关注子宫肌瘤中三类表观基因组变化的最新发现，即异常 DNA 甲基化、组蛋白尾修饰和组蛋白变异交换，以及它们转化为改变的靶基因结构和转录结果。将讨论证明增强子改变的 3D 形状如何调节数百万碱基对之外的基因表达的发现。此外，还将讨论这些发现的转化意义以及平滑肌瘤治疗中的潜在障碍。搜索方法 进行了全面的 PubMed 搜索，以确定包含与审查重点相关的关键字的已发表文章，例如：子宫平滑肌瘤、子宫肌瘤、表观遗传学改变、表观基因组学、干细胞、染色质修饰、细胞外基质 [ECM] 组织、DNA 甲基化、增强子、组蛋白翻译后修饰和失调的基因表达。对 2021 年 9 月之前的文章进行了探索和评估，以确定该领域的相关更新。讨论中重点关注的大多数文章发表于 2015 年至 2021 年之间，尽管 2015 年之前取得的一些重要发现被包括在内以提供背景信息和基础目的。由于篇幅限制或无意遗漏，我们向未能收录其作品的作者致歉。结果 在不改变基础 DNA 序列的情况下，DNA 结构和核小体组蛋白的化学改变现已与子宫平滑肌瘤的表型表现有关。全基因组 DNA 甲基化分析揭示了伴随异常启动子甲基化的抑制或过表达基因的子集。此外，由改变的 3D 染色质结构和组蛋白修饰引起的差异启动子访问在调节被认为与平滑肌瘤病因学有关的关键基因的转录中发挥作用。失调的基因在肿瘤抑制、细胞凋亡、血管生成、ECM 形成、多种癌症相关信号通路和干细胞分化中发挥作用。在改变增强子结构时也观察到异常的 DNA 甲基化或组蛋白修饰，这会导致增强子-启动子接触强度的变化，从而对高迁移率基团 AT-hook 2 的过度表达和在介体复合物亚基 12 突变体肌瘤中发现的基因失调产生新的解释. 虽然已经研究了许多分子机制和表观基因组特征，但在黑人人群中观察到的种族差异的基础仍不清楚。更广泛的意义 缺乏对子宫平滑肌瘤确切发病机制的全面了解，需要引起注意，因为它可以为预防和可行的非手术治疗提供线索。这些发现将拓宽我们对表观基因组学在与子宫平滑肌瘤发展相关的机制中发挥的作用的认识，并突出用于预防和鉴定表观基因组靶标的新方法，以便为这种非常常见的疾病的长期非侵入性治疗选择。更广泛的意义 缺乏对子宫平滑肌瘤确切发病机制的全面了解，需要引起注意，因为它可以为预防和可行的非手术治疗提供线索。这些发现将拓宽我们对表观基因组学在与子宫平滑肌瘤发展相关的机制中发挥的作用的认识，并突出用于预防和鉴定表观基因组靶标的新方法，以便为这种非常常见的疾病的长期非侵入性治疗选择。更广泛的意义 缺乏对子宫平滑肌瘤确切发病机制的全面了解，需要引起注意，因为它可以为预防和可行的非手术治疗提供线索。这些发现将拓宽我们对表观基因组学在与子宫平滑肌瘤发展相关的机制中发挥的作用的认识，并突出用于预防和鉴定表观基因组靶标的新方法，以便为这种非常常见的疾病的长期非侵入性治疗选择。