Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities

Li, Jianjian; Zhe, Ming; Yang, Liuyi; Wang, Tingxuan; Liu, Gaowen; Ma, Qing

doi:10.1016/j.gendis.2022.04.007

Cited by 32 publications

(19 citation statements)

References 196 publications

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“…In addition, XIST is located in the XCI and plays a vital role in random XCI 15,30 . The 5hmC signal peaks in XIST were markedly increased in female samples than in male samples (Figure 1G).…”

Section: Resultsmentioning

confidence: 95%

“…In addition, XIST is located in the XCI and plays a vital role in random XCI. 15,30 The 5hmC signal peaks in XIST were markedly increased in female samples than in male samples (Figure 1G). Further analysis showed that the number of 5hmC reads in the first exon of XIST from F-T were remarkably lower than that in F-L.…”

Section: Hmc Profiles Differ Between Female and Male Hcc Patientsmentioning

confidence: 96%

“…XIST is a lncRNA located in the XCI and an essential mediator of X inactivation 14 . Evidence accumulated suggested that XIST played critical regulatory roles in sex disparities diseases, such as autoimmune diseases, sex disparities cancers, neurological disorders and so on 15 . However, molecular mechanisms still need to be explored in depth.…”

Section: Introductionmentioning

confidence: 99%

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Gender dimorphism in hepatocarcinogenesis—DNA methylation modification regulated X‐chromosome inactivation escape molecule XIST

Dai,

Wang,

Guo

et al. 2023

Clinical & Translational Med

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BackgroundSex disparities constitute a significant issue in hepatocellular carcinoma (HCC). However, the mechanism of gender dimorphism in HCC is still not completely understood.Methods5‐Hydroxymethylcytosine (5hmC)‐Seal technology was utilised to detect the global 5hmC levels from four female and four male HCC samples. Methylation of XIST was detected by Sequenom MassARRAY methylation profiling between HCC tissues (T) and adjacent normal liver tissues (L). The role of Tet methylcytosine dioxygenase 2 (TET2) was investigated using diethylnitrosamine (DEN)‐administered Tet2−/− female mice, which regulated XIST in hepatocarcinogenesis. All statistical analyses were carried out by GraphPad Prism 9.0 and SPSS version 19.0 software.ResultsThe results demonstrated that the numbers of 5hmC reads in the first exon of XIST from female HCC tissues (T) were remarkably lower than that in female adjacent normal liver tissues (L). Correspondingly, DNA methylation level of XIST first exon region was significantly increased in female T than in L. By contrast, no significant change was observed in male HCC patients. Compared to L, the expression of XIST in T was also significantly downregulated. Female patients with higher XIST in HCC had a higher overall survival (OS) and more extended recurrence‐free survival (RFS). Moreover, TET2 can interact with YY1 binding to the promoter region of XIST and maintain the hypomethylation state of XIST. In addition, DEN‐administered Tet2−/− mice developed more tumours than controls in female mice.ConclusionsOur study provided that YY1 and TET2 could interact to form protein complexes binding to the promoter region of XIST, regulating the methylation level of XIST and then affecting the expression of XIST. This research will provide a new clue for studying sex disparities in hepatocarcinogenesis.Highlights XIST was significantly downregulated in HCC tissues and had gender disparity. Methylation levels in the XIST first exon were higher in female HCC tissues, but no significant change in male HCC patients. The TET2–YY1 complex regulate XIST expression in female hepatocytes. Other ways regulate XIST expression in male hepatocytes.

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Section: Resultsmentioning

confidence: 95%

Section: Hmc Profiles Differ Between Female and Male Hcc Patientsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Gender dimorphism in hepatocarcinogenesis—DNA methylation modification regulated X‐chromosome inactivation escape molecule XIST

Dai,

Wang,

Guo

et al. 2023

Clinical & Translational Med

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“…Whether such a masculinization derives from direct effects of androgens and their imbalance with estrogens, or simply arise from the changes in body composition that characterize PCOS [ 1 , 2 , 5 ], are beyond the scope of the present study. Moreover, differences in the genotype and genetic regulators such as non-coding RNAs, including the long non-coding RNA X-inactive specific transcript, might also contribute both to sexual dimorphism and sex-biased disorders [ 52 , 53 ] such as PCOS [ 9 , 54 – 56 ].…”

Section: Discussionmentioning

confidence: 99%

Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS)

et al. 2023

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Background The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity. Methods Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling. Results Obesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts. Conclusions Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.

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“…[10,11] X-inactive-specific transcript (XIST) refers to a class of noncoding RNAs implicated in the differentiation and proliferation of cells. [12] Previous studies have revealed that XIST promotes neurological repair post-SCI by binding to miR-32-5p to modulate Notch-1. [13] LncRNA X-inactive-specific transcript (TSIX) is the lncRNA antisense for XIST and exerts negative regulation on XIST expression.…”

mentioning

confidence: 99%

LncRNA TSIX aggravates spinal cord injury by regulating the PI3K/AKT pathway via the miR‐532‐3p/DDOST axis

Dong

Wei

Zhu

2023

J Biochem & Molecular Tox

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Long noncoding RNA (lncRNA)‐X‐inactive‐specific transcript (TSIX) expression is upregulated in spinal cord tissues following spinal cord injury (SCI). However, the role of lncRNA‐TSIX in SCI remains elusive. SCI animal model was established using C57BL/6 mice. LncRNA TSIX and miR‐532‐3p expression were determined using quantitative reverse transcription polymerase chain reaction (qRT‒PCR). Apoptosis, cell proliferation, and migration were evaluated by transferase dUTP nick end labeling staining, CCK‐8, and Transwell assays, respectively. The interaction of miR‐532‐3p with lncRNA TSIX and DDOST was explored via a dual‐luciferase reporter system. Hematoxylin‐eosin staining and the Basso, Beattie, and Bresnahan locomotor rating (BBB) scale were performed to investigate SCI progression. The expression of the lncRNA TSIX was found to be significantly upregulated in the serum of SCI patients and spinal cord tissues of SCI mice. The overexpression of lncRNA TSIX enhanced spinal cord neural stem cell (SC‐NSC) proliferation and migration in vitro while inhibiting apoptosis and inflammatory cell infiltration in vivo. Moreover, lncRNA TSIX acted as a molecular sponge for miR‐532‐3p, and the knockdown of miR‐532‐3p promoted proliferation and migration and inhibited apoptosis of SC‐NSCs. Moreover, DDOST was found to be the downstream target of miR‐532‐3p, and DDOST overexpression showed a similar effect as miR‐532‐3p silencing on the proliferation, migration, and apoptosis of SC‐NSCs. Furthermore, we found that lncRNA TSIX overexpression promoted the activation of the PI3K/AKT signaling pathway. LncRNA TSIX aggravates SCI by regulating the PI3K/AKT pathway via the miR‐532‐3p/DDOST axis, indicating potential applications for targeted therapy of SCI regeneration.

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Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities

Cited by 32 publications

References 196 publications

Gender dimorphism in hepatocarcinogenesis—DNA methylation modification regulated X‐chromosome inactivation escape molecule XIST

Gender dimorphism in hepatocarcinogenesis—DNA methylation modification regulated X‐chromosome inactivation escape molecule XIST

Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS)

LncRNA TSIX aggravates spinal cord injury by regulating the PI3K/AKT pathway via the miR‐532‐3p/DDOST axis

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