The role of long non-coding RNA H19 in infertility

Peng Y, Yuanyuan Peng, Guo R, Ren-Hao Guo, Renhao Guo, Bei Shi, Da Li
Cell death discovery · 2023 · vol. 9(1) , pp. 268 · doi:10.1038/s41420-023-01567-y · PMID:37507391 · PMC10382492 · W4385349336
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-09 ⓘ

This review examines long non-coding RNA H19's involvement in various infertility causes and its potential as a therapeutic target.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 · read from full text ⓘ

This 2023 review examines the role of the long non-coding RNA H19 in infertility, surveying evidence across conditions including polycystic ovary syndrome, endometriosis, uterine fibroids, diminished ovarian reserve, male factor infertility, and assisted reproductive technology-related pathology, with emphasis on molecular pathways and H19 as a potential target. It reports that H19 has disease-linked expression changes and mechanistic links to processes such as androgen synthesis, granulosa cell proliferation, ovarian remodeling, and methylation-dependent regulation, while noting conflicting findings in animal PCOS models and the need for further work. The paper states that clinical implications of H19 in reproductive endocrine diseases require additional research. Relevance to endometriosis: the review includes a dedicated section on endometriosis, describing menstrual-cycle-dependent endometrial H19 dynamics and reporting higher H19 expression in ectopic endometrium versus normal endometrium in patients with endometriosis, though the paper is mainly a broad infertility-focused review rather than a single-condition mechanistic study.

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Abstract

Infertility is defined as the failure to conceive after at least one year of unprotected intercourse. Long non-coding RNAs (lncRNAs) are transcripts that contain more than 200 nucleotides but do not convert into proteins. LncRNAs, particularly lncRNA H19, have been linked to the emergence and progression of various diseases. This review focuses on the role of H19 in infertility caused by polycystic ovary syndrome, endometriosis, uterine fibroids, diminished ovarian reserve, male factor, and assisted reproductive technology-related pathology, highlighting the potential of H19 as a molecular target for the future treatment of infertility.
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H19

Studies have revealed a potential association between H19 and unexplained infertility. Korucuoglu et al. discovered that abnormally expressed imprinted IGF2 and H19 genes in their endometrium the endometria of patients with unexplained infertility. The expression of IGF2 mRNA was increased (1.5-fold change, P  = 0.015), and H19 expression was lower (4-fold change, P  < 0.0001) in individuals with unexplained infertility [ 70 ]. These findings indicate that additional research on imprinted genes is necessary to understand the molecular epigenetic foundations of unexplained infertility.

Open

What are the characteristics of lncRNA H19-related infertility? What are the etiological molecular mechanisms that involve lncRNA H19 in different causes of infertility? What is the relationship between lncRNA H19 and assisted reproductive technology-related infertility? What are the characteristics of lncRNA H19-related infertility? What are the etiological molecular mechanisms that involve lncRNA H19 in different causes of infertility? What is the relationship between lncRNA H19 and assisted reproductive technology-related infertility?

Facts

LncRNAs play an essential role in the modulation of fertility. LncRNA H19 has been linked to endometriosis, diminished ovarian reserve, polycystic ovary syndrome, uterine fibroids, and male factor infertility. The clinical implications of lncRNA H19 in the treatment of reproductive endocrine diseases needs to be a focus of future research. LncRNAs play an essential role in the modulation of fertility. LncRNA H19 has been linked to endometriosis, diminished ovarian reserve, polycystic ovary syndrome, uterine fibroids, and male factor infertility. The clinical implications of lncRNA H19 in the treatment of reproductive endocrine diseases needs to be a focus of future research.

Structure

The H19 gene belongs to a conserved gene cluster on human chromosome 11p15.5 and on mouse chromosome 7 where insulin-like growth factor 2 (IGF2) also resides [ 12 ]. The gene contains four small introns and five exons. Following transcription, H19 is capped, spliced, polyadenylated, and exported to the cytoplasm [ 13 ]. The imprinting control region (ICR) for the IGF2 and H19 genes is situated 2.5 kb upstream of the H19 promoter region. IGF2 and H19 are expressed by the paternal and maternal alleles, respectively, and are both regulated by the H19-differentially methylated region (DMR) [ 14 ]. The zinc-finger protein CCCTC binding factor (CTCF), which binds to the unmethylated maternal ICR and inhibits IGF2 transcription via a downstream enhancer, controls the reciprocal expression of IGF2 and H19 in the same tissues [ 15 ] (Fig. 1 ). Under normal circumstances, the ICR is hypomethylated at the maternal allele and hypermethylated at the paternal allele; this differential methylation controls the normal expression of IGF2 and H19 [ 16 ]. H19 is highly conserved and produced in the skeletal muscle, heart, uterus, mammary glands, and ovaries throughout the early phase of embryogenesis and in adult tissues [ 17 ]. Fig. 1 H19 expression is controlled by the ICR on the IGF2-H19 locus. A The maternal allele produces H19. The downstream enhancer cannot interact with the IGF2 promoter region because CTCF is bound to the unmethylated ICR, but it can interact with the H19 promoter. B The ICR is hypermethylated, preventing CTCF from binding and enabling interaction between the enhancer and the IGF2 promoter region, which suppresses the production of H19. CTCF CCCTC binding factor; DMR differentially methylated region; E1-5 Exon1-5; ICR imprinting control region, IGF2 insulin-like growth factor 2, lncRNA long non-coding RNA. A The maternal allele produces H19. The downstream enhancer cannot interact with the IGF2 promoter region because CTCF is bound to the unmethylated ICR, but it can interact with the H19 promoter. B The ICR is hypermethylated, preventing CTCF from binding and enabling interaction between the enhancer and the IGF2 promoter region, which suppresses the production of H19. CTCF CCCTC binding factor; DMR differentially methylated region; E1-5 Exon1-5; ICR imprinting control region, IGF2 insulin-like growth factor 2, lncRNA long non-coding RNA.

Conclusion

This review summarizes the role of lncRNA H19 in infertility and its implication in the mechanisms of infertility from diverse causes, such as PCOS, DOR, endometriosis, UFs, ART-related pathology, and infertility caused by male-related variables, for the first time. There is now enough convincing evidence from various sources to make the case that lncRNA H19 is an important factor impacting infertility. These findings offer thought-provoking insights into the occurrence and progression of infertility and new molecular targets for prevention and treatment. However, the mechanism by which H19 regulates downstream molecules has not yet been fully explored. Nevertheless, the biological potential of lncRNAs is clear, and the clinical application of H19 and its application in the treatment of reproductive endocrine diseases will be the focus of future research.

Introduction

Infertility is defined as the absence of pregnancy after at least one year of unprotected intercourse. It has become a global health problem that affects 15% of reproductive-age couples [ 1 ]. Infertility can occur in both males and females. While approximately 85% of infertility cases are caused by ovulation abnormalities, male-factor infertility, and tubal illness, unexplained infertility affects remaining 15% of infertile couples [ 2 ]. Epigenetics has provided recent and new insights into infertility. Epigenetic modifications, characterized by histone modifications, DNA methylation, chromatin remodeling, and RNA-based mechanisms, play crucial roles in many biological processes, including spermatogenesis and ovulation [ 3 – 5 ]. An increasing volume of research illustrates that long non-coding RNAs (lncRNAs), including lncRNA H19, play an essential role in the modulation of fertility [ 6 ]. H19 has been linked to several reproduction-related diseases, such as endometriosis [ 7 ], diminished ovarian reserve (DOR) [ 8 ], polycystic ovary syndrome (PCOS) [ 9 ], uterine fibroids (UFs) [ 10 ], and male factor infertility [ 11 ]. This review highlights the specific effects of lncRNA H19 on both female and male infertility, summarizes the role of H19 in infertility, and provides a theoretical foundation for its potential use as a novel molecular target for infertility treatment.

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