Stability of XIST repression in relation to genomic imprinting following global genome demethylation in a human cell line

Araújo, Érica Sara Souza de; Vasques, Luciana dos Reis; Stabellini, Raquel; Krepischi, Ana Cristina Victorino; Pereira, Lygia V.

doi:10.1590/1414-431x20144058

Cited by 2 publications

(1 citation statement)

References 31 publications

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“…It has been well established that DNA hypomethylation can activate XIST gene expression. The DNA demethylating agent 5-Aza-2′-deoxycytidine (5-aza) can lead to the demethylation of the XIST DMR and XIST reactivation in somatic cells ( Hansen et al, 1998 ; Tinker and Brown, 1998 ; de Araujo et al, 2014 ). Since AFF3 can bind to the methylated XIST DMR and repress XIST gene expression, we speculated that the binding of AFF3 might rely on the methylation status of the XIST DMR.…”

Section: Resultsmentioning

confidence: 99%

AFF3-DNA methylation interplay in maintaining the mono-allelic expression pattern of XIST in terminally differentiated cells

Zhang

Wang

Liu

et al. 2018

Journal of Molecular Cell Biology

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X chromosome inactivation and genomic imprinting are two classic epigenetic regulatory processes that cause mono-allelic gene expression. In female mammals, mono-allelic expression of the long non-coding RNA gene X-inactive specific transcript (XIST) is essential for initiation of X chromosome inactivation upon differentiation. We have previously demonstrated that the central factor of super elongation complex-like 3 (SEC-L3), AFF3, is enriched at gamete differentially methylated regions (DMRs) of the imprinted loci and regulates the imprinted gene expression. Here, we found that AFF3 can also bind to the DMR downstream of the XIST promoter. Knockdown of AFF3 leads to de-repression of the inactive allele of XIST in terminally differentiated cells. In addition, the binding of AFF3 to the XIST DMR relies on DNA methylation and also regulates DNA methylation level at DMR region. However, the KAP1-H3K9 methylation machineries, which regulate the imprinted loci, might not play major roles in maintaining the mono-allelic expression pattern of XIST in these cells. Thus, our results suggest that the differential mechanisms involved in the XIST DMR and gDMR regulation, which both require AFF3 and DNA methylation.

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Section: Resultsmentioning

confidence: 99%

AFF3-DNA methylation interplay in maintaining the mono-allelic expression pattern of XIST in terminally differentiated cells

Zhang

Wang

Liu

et al. 2018

Journal of Molecular Cell Biology

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Integrative Single Cell Multiomic Profiling Analysis Reveals HOX-PBX Gene Regulatory Network Contributing to the Survival of mTOR Hyperactive Cells

Olatoke

Wagner

Guo

et al. 2022

Preprint

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Lymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM is characterized by the infiltration of the lungs by abnormally proliferating smooth muscle-like cells of unknown origin via an estrogen-dependent metastatic mechanism. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. Sirolimus, an FDA approved mTORC1 inhibitor and current best-choice medication for LAM stabilizes lung function in most LAM patients. However, it requires sustained application and remains inefficacious in some patients. The greatest barriers to finding a cure for LAM include its undetermined origin and unclear underlying pathogenesis. Our study aims to advance knowledge on the origin of LAM, and ultimately serve as a premise for the development of novel therapeutic targets for LAM. Single cell RNA sequencing (scRNA-seq) is a powerful tool in biomedical research that informs gene expression differences at the cellular level and may provide insights into the most fundamental origin of LAM cells. Our scRNA-seq analysis of LAM cells revealed a unique population of cells (LAMCORE), expressing uterine-similar homeobox transcription factors (HOX) and Pre-B-cell leukemia homeobox 1 (PBX1), which are absent in normal lung, suggesting that the uterus is the primary origin of LAM. PBX1 is a transcription factor critical for female reproductive tract development and maintenance, and its overexpression is implicated in some female reproductive cancers. In this study we hypothesize that PBX1 promotes survival and lung colonization of LAM (TSC2-null) cells. Using LAM patient-derived cells, we validated the transcriptional profile, gene expression and protein levels of PBX1. We have the first functional evidence that PBX1 and its downstream targets are upregulated in LAM cells. In a mouse model of LAM, we monitored the effect of suppression of PBX1 by short hairpin RNA-mediated gene silencing on lung colonization and tumor growth. We also found that pharmacological suppression of PBX1 attenuates LAM lung colonization and promotes death of LAM cells in vivo and vitro. Our data collectively suggests that PBX1 is a critical regulator of LAM progression.

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Stability of XIST repression in relation to genomic imprinting following global genome demethylation in a human cell line

Cited by 2 publications

References 31 publications

AFF3-DNA methylation interplay in maintaining the mono-allelic expression pattern of XIST in terminally differentiated cells

AFF3-DNA methylation interplay in maintaining the mono-allelic expression pattern of XIST in terminally differentiated cells

Integrative Single Cell Multiomic Profiling Analysis Reveals HOX-PBX Gene Regulatory Network Contributing to the Survival of mTOR Hyperactive Cells

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