ZNF423: Transcriptional modulation in development and cancer

Harder, Lena; Puller, Ann-Christin; Horstmann, Martin

doi:10.4161/23723548.2014.969655

Cited by 19 publications

(18 citation statements)

References 70 publications

(110 reference statements)

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“…Consistent with our findings, HIF-1α has been associated with platinum resistance in a variety of cancers, including ovarian [13]. Moreover, ESR1 and ZNF423 have role in cancer cell proliferation [14,15] and were significantly associated with platinumsensitive tumors.…”

Section: Clinical Outcome Based On Inferred Tf Activitiessupporting

confidence: 90%

Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers

Osmanbeyoglu

Shimizu

Rynne-Vidal

et al. 2018

Preprint

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Epigenomic data on transcription factor occupancy and chromatin accessibility can elucidate the developmental origin of cancer cells and reveal the enhancer landscape of key oncogenic transcriptional regulators. However, in many cancers, epigenomic analyses have been limited, and computational methods to infer regulatory networks in tumors typically use expression data alone, or rely on transcription factor (TF) motifs in annotated promoter regions. Here, we develop a novel machine learning strategy called PSIONIC (patient-specific inference of networks informed by chromatin) to combine cell line chromatin accessibility data with large tumor expression data sets and model the effect of enhancers on transcriptional programs in multiple cancers. We generated a new ATAC-seq data set profiling chromatin accessibility in gynecologic and basal breast cancer cell lines and applied PSIONIC to 723 RNA-seq experiments from ovarian, uterine, and basal breast tumors as All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/333757 doi: bioRxiv preprint first posted online May. 30, 2018; 2 well as 96 cell line RNA-seq profiles. Our computational framework enables us to share information across tumors to learn patient-specific inferred TF activities, revealing regulatory differences between and within tumor types. Many of the identified TF regulators were significantly associated with survival outcome in basal breast, uterine serous and endometrioid carcinomas. Moreover, PSIONIC-predicted activity for MTF1 in cell line models correlated with sensitivity to MTF1 inhibition. Therefore computationally dissecting the role of TFs in gynecologic cancers may ultimately advance personalized therapy.

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Section: Clinical Outcome Based On Inferred Tf Activitiessupporting

confidence: 90%

Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers

Osmanbeyoglu

Shimizu

Rynne-Vidal

et al. 2018

Preprint

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“…5 c). ZNF423 has previously been reported to interact with EBF1 [25–28]. Here we show a majority of M3 genes with ZNF423-binding motifs also feature EBF1 motifs (Fig.…”

Section: Resultssupporting

confidence: 67%

“…Although the effects of ZNF423 and EBF1 on placental gene regulation remain largely unexplored, ZNF423 appears to be a multi-functional transcription factor associated with B cell regulation, retinoic acid signalling, notch signalling, DNA damage response pathways, adipogenesis and cancer [25]. Furthermore, homozygous mutation in the homologous gene in mice ( Zfp423 ) results in smaller ataxic pups who die shortly after birth [38].…”

Section: Discussionmentioning

confidence: 99%

Placental transcriptome co-expression analysis reveals conserved regulatory programs across gestation

et al. 2017

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BackgroundMammalian development in utero is absolutely dependent on proper placental development, which is ultimately regulated by the placental genome. The regulation of the placental genome can be directly studied by exploring the underlying organisation of the placental transcriptome through a systematic analysis of gene-wise co-expression relationships.ResultsIn this study, we performed a comprehensive analysis of human placental co-expression using RNA sequencing and intergrated multiple transcriptome datasets spanning human gestation. We identified modules of co-expressed genes that are preserved across human gestation, and also identifed modules conserved in the mouse indicating conserved molecular networks involved in placental development and gene expression patterns more specific to late gestation. Analysis of co-expressed gene flanking sequences indicated that conserved co-expression modules in the placenta are regulated by a core set of transcription factors, including ZNF423 and EBF1. Additionally, we identified a gene co-expression module enriched for genes implicated in the pregnancy pathology preeclampsia. By using an independnet transcriptome dataset, we show that these co-expressed genes are differentially expressed in preeclampsia.ConclusionsThis study represents a comprehensive characterisation of placental co-expression and provides insight into potential transcriptional regulators that govern conserved molecular programs fundamental to placental development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3384-9) contains supplementary material, which is available to authorized users.

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“…The opposite regulations of ZNF423 and BRCA1 expression was observed when treated with either E2 or 4-OH-TAM for the variant SNP. Although ZNF423 functions as a DNA-binding transcription factor in several signaling pathways [ 9 , 10 ], its role in breast cancer and treatment response remains unknown. We have shown that ZNF423 directly regulated BRCA1 expression and influenced its function in DNA damage repair [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Calmodulin-like protein 3 is an estrogen receptor alpha coregulator for gene expression and drug response in a SNP, estrogen, and SERM-dependent fashion

et al. 2017

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BackgroundWe previously performed a case–control genome-wide association study in women treated with selective estrogen receptor modulators (SERMs) for breast cancer prevention and identified single nucleotide polymorphisms (SNPs) in ZNF423 as potential biomarkers for response to SERM therapy. The ZNF423rs9940645 SNP, which is approximately 200 bp away from the estrogen response elements, resulted in the SNP, estrogen, and SERM-dependent regulation of ZNF423 expression and, “downstream”, that of BRCA1.MethodsElectrophoretic mobility shift assay–mass spectrometry was performed to identify proteins binding to the ZNF423 SNP and coordinating with estrogen receptor alpha (ERα). Clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing was applied to generate ZR75-1 breast cancer cells with different ZNF423 SNP genotypes. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to SERMs and poly(ADP-ribose) polymerase (PARP) inhibitors.ResultsWe identified calmodulin-like protein 3 (CALML3) as a key sensor of this SNP and a coregulator of ERα, which contributes to differential gene transcription regulation in an estrogen and SERM-dependent fashion. Furthermore, using CRISPR/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to SERMs and PARP inhibitors, alone or in combination, were observed not only in cells but also in a mouse xenograft model.ConclusionsOur results have demonstrated the mechanism by which the ZNF423 rs9940645 SNP might regulate gene expression and drug response as well as its potential role in achieving more highly individualized breast cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0890-x) contains supplementary material, which is available to authorized users.

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ZNF423: Transcriptional modulation in development and cancer

Cited by 19 publications

References 70 publications

Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers

Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers

Placental transcriptome co-expression analysis reveals conserved regulatory programs across gestation

Calmodulin-like protein 3 is an estrogen receptor alpha coregulator for gene expression and drug response in a SNP, estrogen, and SERM-dependent fashion

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