An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations

Makowski, Matthew; Willems, Esther; Fang, Jun; Choi, Jiyeon; Zhang, Tongwu; Jansen, Pascal W.T.C.; Brown, Kevin M.; Vermeulen, Michiel

doi:10.1002/pmic.201500327

Cited by 54 publications

(73 citation statements)

References 35 publications

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“…hTERT is the major determinant of telomerase activity, and it plays a key role in cellular immortalization and the development and progression of human cancers. The reactivation of telomerase activity is observed in approximately 90% of human cancers, enabling cells to overcome replicative senescence and to escape apoptosis, which are fundamental steps in the initiation of malignant transformation[146,147]. The precise mechanism behind the reactivation of telomerase activity in cancer remains elusive, but it likely involves multiple changes that occur during the progression of cancer, including mutations and chromosomal rearrangements[148].…”

Section: Somatic Mutations In Hccmentioning

confidence: 99%

Genetic alterations in hepatocellular carcinoma: An update

Niu¹,

Niu²,

Wang³

2016

WJG

137

108

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.

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Section: Somatic Mutations In Hccmentioning

confidence: 99%

Genetic alterations in hepatocellular carcinoma: An update

Niu¹,

Niu²,

Wang³

2016

WJG

137

108

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“…Phospho-flow analyses We aimed to mechanistically understand how this enhancer region is impacting RasGRP1 expression and we postulated that factors binding to the RasGRP1 enhancer may be distinct in clones Enh-i and Enh-ii. To identify transcription factors regulating RASGRP1 expression by binding autoimmunityassociated enhancer 1, we performed AP-MS (affinity purification mass spectrometry) analysis [26].…”

Section: -Suppl a Bmentioning

confidence: 99%

“…DNA affinity purifications and on-bead trypsin digestion was performed as described [26]. Tryptic peptides from SNP variant pull-downs were desalted using Stage (stop and go extraction) tips [40], and then subjected to stable isotope di-methyl labeling [41] on the Stage tips.…”

Section: Dna Affinity Purification and Lc-ms Analysismentioning

confidence: 99%

Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Baars

Douma

Simeonov

et al. 2019

Preprint

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RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development.RASGRP1-deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4 + T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunityassociated SNPs. CRISPR-Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4 + T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.

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“…Experimental confirmation came through specific binding of an multimeric ETS family member, GA‐binding protein, alpha subunit (GABPA) as a heteromeric complex with GABP1 in cooperation with native sites in proximity to the de novo sites generated by the TERT promoter mutations . A study based on a proteome‐wide survey showed a complex competitive recruitment of GABPA enabled by spatial arrangement of native and newly created ETS sites through displacement of initially recruited ELF1 transcription factors at the latter sites . Another study showed requirement of non‐canonical NF‐kB signaling involving cooperativity between p52/RelB and ETS1 for binding at the site created specifically by −146 C > T, one of the main TERT promoter mutations .…”

Section: Regulatory Mutations: Mechanism Of Effectmentioning

confidence: 99%

“…116 A study based on a proteomewide survey showed a complex competitive recruitment of GABPA enabled by spatial arrangement of native and newly created ETS sites through displacement of initially recruited ELF1 transcription factors at the latter sites. 117 Another study showed requirement of non-canonical NF-kB signaling involving cooperativity between p52/RelB and ETS1 for binding at the site created specifically by 2146 C > T, one of the main TERT promoter mutations. 118 Mechanistic studies have shown the TERT promoter mutations to cause massive epigenetic change on the mutant allele from H3K27me3 to H3K4me2/3, a mark of active chromatin, along with recruitment of pol II following the binding of GABPA/B1 complex leading to monoallelic expression.…”

Section: Regulatory Mutations: Mechanism Of Effectmentioning

confidence: 99%

Altered TERT promoter and other genomic regulatory elements: occurrence and impact

Heidenreich

Kumar

2017

Intl Journal of Cancer

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Study of genetic alterations, inherited or acquired, that increase the risk or drive cancers and many other diseases had remained mostly confined to coding sequences of the human genome. Data from genome wide associations studies, development of the Encyclopedia of DNA Elements (ENCODE), and a spurt in detection of driver somatic mutations have shifted focus towards noncoding regions of the human genome. The majority of genetic variants robustly associated with cancers and other syndromes identified through genome wide studies are located within noncoding regulatory regions of the genome. Genome wide techniques have put an emphasis on the role of three-dimensional chromosomal structures and cis-acting elements in regulations of different genes. The variants within noncoding genomic regions can potentially alter a number of regulatory elements including promoters, enhancers, insulators, noncoding long RNAs and others that affect cancers and various diseases through altered expression of critical genes. With effect of genetic alterations within regulatory elements dependent on other partner molecules like transcription factors and histone marks, an understanding of such modifications can potentially identify extended therapeutic targets. That concept has been augmented by the detection of driver somatic noncoding mutations within the promoter region of the telomerase reverse transcriptase (TERT) gene in different cancers. The acquired somatic noncoding mutations within different regulatory elements are now being reported in different cancers with an increased regularity. In this review we discuss the occurrence and impact of germline and somatic alterations within the TERT promoter and other genomic regulatory elements.

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An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations

Cited by 54 publications

References 35 publications

Genetic alterations in hepatocellular carcinoma: An update

Genetic alterations in hepatocellular carcinoma: An update

Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Altered TERT promoter and other genomic regulatory elements: occurrence and impact

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