Somatic XIST activation and features of X chromosome inactivation in male human cancers

Sadagopan, Ananthan; Nasim, Imran Tariq; Li, Jiao; Achom, Mingkee; Chen, Ken; Viswanathan, Srinivas R.

doi:10.1016/j.cels.2022.10.002

Cited by 17 publications

(9 citation statements)

References 82 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%

“…There were also many studies indicating that XIST had the role of the oncogene. An analysis of published sequencing data on cancer tissues revealed that XIST was activated and expressed in various male tumours characteristics of XCI 30 . Much evidence shows that XIST plays a vital role in the proliferation, invasion, migration, apoptosis and chemosensitivity of non‐small‐cell lung cancer (NSCLC) cells 50,51 .…”

Section: Discussionmentioning

confidence: 99%

“…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: 97%

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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: Discussionmentioning

confidence: 99%

Section: Hmc Profiles Differ Between Female and Male Hcc Patientsmentioning

confidence: 97%

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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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“…XIST is essential for X chromosome inactivation, and it is only expressed in female tissues ( 114 ). Recently, somatic activation of XIST was identified in a subset of male cancers ( 115 ). In ovarian cancer, XIST was shown to regulate the miR-506-3p/FOXP1 axis, in turn regulating autophagy and carboplatin resistance ( 116 ).…”

Section: Resultsmentioning

confidence: 99%

lncHUB2: aggregated and inferred knowledge about human and mouse lncRNAs

et al. 2023

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Long non-coding ribonucleic acids (lncRNAs) account for the largest group of non-coding RNAs. However, knowledge about their function and regulation is limited. lncHUB2 is a web server database that provides known and inferred knowledge about the function of 18 705 human and 11 274 mouse lncRNAs. lncHUB2 produces reports that contain the secondary structure fold of the lncRNA, related publications, the most correlated coding genes, the most correlated lncRNAs, a network that visualizes the most correlated genes, predicted mouse phenotypes, predicted membership in biological processes and pathways, predicted upstream transcription factor regulators, and predicted disease associations. In addition, the reports include subcellular localization information; expression across tissues, cell types, and cell lines, and predicted small molecules and CRISPR knockout (CRISPR-KO) genes prioritized based on their likelihood to up- or downregulate the expression of the lncRNA. Overall, lncHUB2 is a database with rich information about human and mouse lncRNAs and as such it can facilitate hypothesis generation for many future studies. The lncHUB2 database is available at https://maayanlab.cloud/lncHUB2. Database URL: https://maayanlab.cloud/lncHUB2

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“…5). This circumstance is relevant to multiple fields and studies, such as in models of lupus ( 52, 54 ), certain cancers ( 71, 72 ), and other autoimmune diseases ( 73 ). As shown in this study, aberrant Xist expression in males causes a decrease in surface Igα expression due to an accumulation of pSTAT3 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Maternal infection causes dysfunctional BCR signaling in male offspring due to aberrant Xist expression

Gibbs

Oviedo

Ondigo

et al. 2023

Preprint

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Infections during pregnancy with pathogens such as helminths correlate with altered immune responses to common childhood immunizations. However, the molecular mechanisms that underlie this remain unknown. Using our murine model of maternal schistosomiasis, when immunized, males from infected mothers had a lower frequency of antigen-specific germinal center B cells and downregulation of transcripts downstream of BCR signaling compared to males from uninfected mothers. This is driven by a reduction in developing B cell populations within the bone marrow of pups from infected mothers. Males from infected mothers were impacted to a greater extent than their female littermate counterparts. We found this defect to be caused by aberrant expression of the long non-coding RNA Xist in males leading to dysregulated Igalpha expression on developing B cells. This, for the first time, links dysfunctional BCR signaling with Xist expression, while also proposing a detrimental function for Xist expression in males.

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Somatic XIST activation and features of X chromosome inactivation in male human cancers

Cited by 17 publications

References 82 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

lncHUB2: aggregated and inferred knowledge about human and mouse lncRNAs

Maternal infection causes dysfunctional BCR signaling in male offspring due to aberrant Xist expression

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