Architects of the genome: CHD dysfunction in cancer, developmental disorders and neurological syndromes

Li, Wangzhi; Mills, Alea A.

doi:10.2217/epi.14.31

Cited by 37 publications

(46 citation statements)

References 147 publications

(227 reference statements)

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“…It is known that some CHD dysfunction occurs in cancer [37]. In silico analysis in the present showed the higher expression of CHD7 and CHD9 in brain tumor (Additional file 7: Figure S6).…”

Section: Discussionmentioning

confidence: 59%

CHD7 promotes proliferation of neural stem cells mediated by MIF

et al. 2016

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Macrophage migration inhibitory factor (MIF) plays an important role in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs); however, the downstream effectors of this factor remain unknown. Here, we show that MIF increases the expression of Pax6 and Chd7 in NSPCs in vitro. During neural development, the chromatin remodeling factor Chd7 (chromatin helicase-DNA-binding protein 7) is expressed in the ventricular zone of the telencephalon of mouse brain at embryonic day 14.5, as well as in cultured NSPCs. Retroviral overexpression of Pax6 in NSPCs increased Chd7 gene expression. Lentivirally-expressed Chd7 shRNA suppressed cell proliferation and neurosphere formation, and inhibited neurogenesis in vitro, while decreasing gene expression of Hes5 and N-myc. In addition, CHD7 overexpression increased cell proliferation in human embryonic stem cell-derived NSPCs (ES-NSPCs). In Chd7 mutant fetal mouse brains, there were fewer intermediate progenitor cells (IPCs) compared to wildtype littermates, indicating that Chd7 contributes to neurogenesis in the early developmental mouse brain. Furthermore, in silico database analysis showed that, among members of the CHD family, CHD7 is highly expressed in human gliomas. Interestingly, high levels of CHD7 gene expression in human glioma initiating cells (GICs) compared to normal astrocytes were revealed and gene silencing of CHD7 decreased GIC proliferation. Collectively, our data demonstrate that CHD7 is an important factor in the proliferation and stemness maintenance of NSPCs, and CHD7 is a promising therapeutic target for the treatment of gliomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0275-6) contains supplementary material, which is available to authorized users.

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“…It is known that some CHD dysfunction occurs in cancer [37]. In silico analysis in the present showed the higher expression of CHD7 and CHD9 in brain tumor (Additional file 7: Figure S6).…”

Section: Discussionmentioning

confidence: 59%

CHD7 promotes proliferation of neural stem cells mediated by MIF

et al. 2016

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“…CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer (Colbert et al ., ). Furthermore, loss‐of‐function mutations in several CHD genes are associated with developmental disorders and intellectual disability (Li and Mills, ). Notably, de novo mutations in CHD7 cause the CHARGE syndrome (coloboma, heart defects, atresia of the choanae, retarded growth and development, genitourinary hypoplasia, and ear abnormalities, including deafness and vestibular disorders), which is characterized by a unique combination of organ anomalies (Basson and van Ravenswaaij‐Arts, ).…”

Section: Introductionmentioning

confidence: 99%

Genotranscriptomic meta‐analysis of the CHD family chromatin remodelers in human cancers – initial evidence of an oncogenic role for CHD7

et al. 2017

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Chromodomain helicase DNA binding proteins (CHDs) are characterized by N‐terminal tandem chromodomains and a central adenosine triphosphate‐dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10 000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amplified and mutated, whereas CHD3 was the most deleted across the majority of tumor types, including breast cancer. Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis. CHD7 is required to maintain open, accessible chromatin, thus providing fine‐tuning of transcriptional regulation of certain classes of genes. We found that CHD7 expression was positively correlated with a small subset of classical oncogenes, notably NRAS, in breast cancer. Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets, including NRAS, in breast cancer cell lines. Thus, our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer.

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“…Although other CHD proteins have yet to be linked to human genetic disease, it has been demonstrated that CHD4 and CHD5 carry out important functions in neurogenesis [33,34]. Although beyond the scope of this communication, the contribution of CHD dysfunction in the etiology of cancer has been long recognized [35].…”

Section: Chd Family and Genetic Diseasementioning

confidence: 92%