Nuclear factor one transcription factors: Divergent functions in developmental versus adult stem cell populations

Harris, Lachlan; Genovesi, Laura A.; Gronostajski, Richard M.; Wainwright, Brandon; Piper, Michael

doi:10.1002/dvdy.24182

Cited by 69 publications

(61 citation statements)

References 98 publications

(185 reference statements)

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“…NFIs play different roles depending on cellular or tissue context. For example, NFIs that promote differentiation during development can also promote survival of stem cells in adults . In cancer, NFIs can have oncogenic roles (as demonstrated here) or tumour suppressor roles (for recent reviews, see refs 9 and 10).…”

Section: Discussionmentioning

confidence: 79%

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Liu

Jain

et al. 2018

The Journal of Pathology

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Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and poor prognosis. There is an urgent need to identify and understand the key factors and signalling pathways driving TNBC tumour progression, relapse, and treatment resistance. In this study, we report that gene copy numbers and expression levels of nuclear factor IB (NFIB), a recently identified oncogene in small cell lung cancer, are preferentially increased in TNBC compared to other breast cancer subtypes. Furthermore, increased levels of NFIB are significantly associated with high tumour grade, poor prognosis, and reduced chemotherapy response. Concurrent TP53 mutations and NFIB overexpression (z‐scores > 0) were observed in 77.9% of TNBCs, in contrast to 28.5% in non‐TNBCs. Depletion of NFIB in TP53‐mutated TNBC cell lines promotes cell death, cell cycle arrest, and enhances sensitivity to docetaxel, a first‐line chemotherapeutic drug in breast cancer treatment. Importantly, these alterations in growth properties were accompanied by induction of CDKN1A, the gene encoding p21, a downstream effector of p53. We show that NFIB directly interacts with the CDKN1A promoter in TNBC cells. Furthermore, knockdown of combined p21 and NFIB reverses the docetaxel‐induced cell growth inhibition observed upon NFIB knockdown, indicating that NFIB's effect on chemotherapeutic drug response is mediated through p21. Our results indicate that NFIB is an important TNBC factor that drives tumour cell growth and drug resistance, leading to poor clinical outcomes. Thus, targeting NFIB in TP53‐mutated TNBC may reverse oncogenic properties associated with mutant p53 by restoring p21 activity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 79%

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Liu

Jain

et al. 2018

The Journal of Pathology

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“…Increased Nfib occupancy in the absence of increased accessibility is only weakly associated with increased gene expression, while Nfib-driven increases in distal accessibility is associated with upregulation of nearby genes (Figure 7D and S7E-F). Nfib has diverse functions and has been shown to both promote cell differentiation during development and maintain populations of stem cells in adult tissues (Harris et al 2015; Gronostajski 2000; Chang et al 2013). An implication of our study is that maintenance of open chromatin architecture by Nfib may promote varied functional outcomes through combinatorial binding of nearby transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Denny

Yang

Chuang

et al. 2016

Cell

331

367

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SUMMARY Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.

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“…The NFI class comprises four members (NFIA, NFIB, NFIC, and NFIX) and the SMAD class has eight of them (SMAD1 to 8/9) in mammals. All have important roles in various processes [166] NFI homo/heterodimers bind DNA at the palindromic TTGGC(N5)GCCAA sequence to contribute to transcriptional activation or repression. NFIX missense and dominant-negative mutations cause Sotos and Marshall-Smith syndrome, respectively.…”

Section: Transcription Factors With a β-Hairpin Exposed By A α/β-Smentioning

confidence: 99%

Transcriptional control of chondrocyte specification and differentiation

Liu

Samsa

Zhou

et al. 2017

Seminars in Cell & Developmental Biology

145

112

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A milestone in the evolutionary emergence of vertebrates was the invention of cartilage, a tissue that has key roles in modeling, protecting and complementing the bony skeleton. Cartilage is elaborated and maintained by chondrocytes. These cells derive from multipotent skeletal progenitors and they perform highly specialized functions as they proceed through sequential lineage commitment and differentiation steps. They form cartilage primordia, the primary skeleton of the embryo. They then transform these primordia either into cartilage growth plates, temporary drivers of skeletal elongation and endochondral ossification, or into permanent tissues, namely articular cartilage. Chondrocyte fate decisions and differentiated activities are controlled by numerous extrinsic and intrinsic cues, and they are implemented at the gene expression level by transcription factors. The latter are the focus of this review. Meritorious efforts from many research groups have led over the last two decades to the identification of dozens of key chondrogenic transcription factors. These regulators belong to all types of transcription factor families. Some have master roles at one or several differentiation steps. They include SOX9 and RUNX2/3. Others decisively assist or antagonize the activities of these masters. They include TWIST1, SOX5/6, and MEF2C/D. Many more have tissue-patterning roles and regulate cell survival, proliferation and the pace of cell differentiation. They include, but are not limited to, homeodomain-containing proteins and growth factor signaling mediators. We here review current knowledge of all these factors, one superclass, class, and family at a time. We then compile all knowledge into transcriptional networks. We also identify remaining gaps in knowledge and directions for future research to fill these gaps and thereby provide novel insights into cartilage disease mechanisms and treatment options.

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Nuclear factor one transcription factors: Divergent functions in developmental versus adult stem cell populations

Cited by 69 publications

References 98 publications

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Transcriptional control of chondrocyte specification and differentiation

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