Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum

Frank, Christopher L.; Liu, Fang; Wijayatunge, Ranjula; Song, Lingyun; Biegler, Matthew T.; Yang, Marty G.; Vockley, Christopher M.; Safi, Alexias; Gersbach, Charles A.; Crawford, Gregory E.; West, Anne E.

doi:10.1038/nn.3995

Cited by 146 publications

(237 citation statements)

References 66 publications

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“…Another commonly used activator is the p65 subunit of the human NF-κB complex 50 that has been tethered to ZFPs 51 , TALEs 41, 42 , and dCas9 45 . Gene induction by VP64 and p65 is generally strongest when effector domains are targeted upstream of transcription start sites and within promoter regions 45 , although targeting downstream of TSSs and at distal enhancers can also be effective 46, 47, 52–54 .…”

Section: Site-specific Epigenome Editingmentioning

confidence: 99%

“…It is also a critical area of future research since the vast majority of genetic variation associated with complex disease lies in these regions 5 . The programmable nature of epigenome editing tools uniquely enables the interrogation of regulatory regions to uncover the biological role of unique genomic elements in the native genomic context 46–48, 54, 73, 79, 86 .…”

Section: Modulating Regulatory Elements and Higher Order Chromatin Ormentioning

confidence: 99%

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Editing the epigenome: technologies for programmable transcription and epigenetic modulation

et al. 2016

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Gene regulation is a highly complex and tightly controlled process that defines cell identity, health, and response to environmental signals. Technologies for precisely perturbing gene regulation are critical for improving our understanding of its coordination and for manipulating pathways for applications in biotechnology and medicine. Recently developed DNA-targeting platforms, including zinc finger proteins, TALEs, and CRISPR/Cas9, have enabled the recruitment of transcriptional modulators and epigenome-modifying factors to any genomic site. These technologies are generating novel insights into the function of epigenetic marks and the role of genome structure in gene expression. Additionally, custom transcriptional and epigenetic regulation is facilitating refined control over cell function and decision-making. The unique properties of the CRISPR/Cas9 system have also created new opportunities for multiplexing targets and manipulating complex gene expression patterns, as well as high-throughput genetic screens. This review summarizes recent technology developments in this area and their applications to modern biomedical challenges. We also discuss remaining limitations and necessary future directions for this field.

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Section: Site-specific Epigenome Editingmentioning

confidence: 99%

Section: Modulating Regulatory Elements and Higher Order Chromatin Ormentioning

confidence: 99%

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

et al. 2016

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“…While this manuscript was being revised, Frank et al published ChIP-seq data for Zic1 and Zic2 in post-natal day-7 mouse cerebellum (Frank et al, 2015). Given the functional relationship between Brn2 and Zic1 described in this paper, we integrated this new public ChIP-seq data with the Brn2 data in our paper.…”

Section: Note Added In Proofmentioning

confidence: 99%

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Urban

Kobi

Ennen

et al. 2015

Journal of Cell Science

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Mouse embryonic stem cells (ESCs) treated with all-trans retinoic acid differentiate into a homogenous population of glutamatergic neurons. Although differentiation is initiated through activation of target genes by the retinoic acid receptors, the downstream transcription factors specifying neuronal fate are less well characterised. Here, we show that the transcription factor Brn2 (also known as Pou3f2) is essential for the neuronal differentiation programme. By integrating results from RNA-seq following Brn2 silencing with results from Brn2 ChIP-seq, we identify a set of Brn2 target genes required for the neurogenic programme. Further integration of Brn2 ChIP-seq data from retinoicacid-treated ESCs and P19 cells with data from ESCs differentiated into neuronal precursors by Fgf2 treatment and that from fibroblasts trans-differentiated into neurons by ectopic Brn2 expression showed that Brn2 occupied a distinct but overlapping set of genomic loci in these differing conditions. However, a set of common binding sites and target genes defined the core of the Brn2-regulated neuronal programme, among which was that encoding the transcription factor Zic1. Small hairpin RNA (shRNA)-mediated silencing of Zic1 prevented ESCs from differentiating into neuronal precursors, thus defining a hierarchical Brn2-Zic1 axis that is essential to specify neural fate in retinoic-acid-treated ESCs.

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“…Both Zic1- and Gmnn-associated locations in NE were also enriched for Zic1 consensus binding sequence motifs, suggesting that Gmnn-Zic1 functional cooperation could regulate sets of genes involved in neural fate acquisition. While Zic1 targets in post-natal cerebellar development had been determined4243, Zic1-associated locations during neural cell fate acquisition were unknown. Therefore, we conducted Zic1 ChIP-seq during neural fate acquisition in this study.…”

Section: Discussionmentioning

confidence: 99%

Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1

Sankar¹,

Yellajoshyula²,

Zhang³

et al. 2016

Sci Rep

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Neural cell fate acquisition is mediated by transcription factors expressed in nascent neuroectoderm, including Geminin and members of the Zic transcription factor family. However, regulatory networks through which this occurs are not well defined. Here, we identified Geminin-associated chromatin locations in embryonic stem cells and Geminin- and Zic1-associated locations during neural fate acquisition at a genome-wide level. We determined how Geminin deficiency affected histone acetylation at gene promoters during this process. We integrated these data to demonstrate that Geminin associates with and promotes histone acetylation at neurodevelopmental genes, while Geminin and Zic1 bind a shared gene subset. Geminin- and Zic1-associated genes exhibit embryonic nervous system-enriched expression and encode other regulators of neural development. Both Geminin and Zic1-associated peaks are enriched for Zic1 consensus binding motifs, while Zic1-bound peaks are also enriched for Sox3 motifs, suggesting co-regulatory potential. Accordingly, we found that Geminin and Zic1 could cooperatively activate the expression of several shared targets encoding transcription factors that control neurogenesis, neural plate patterning, and neuronal differentiation. We used these data to construct gene regulatory networks underlying neural fate acquisition. Establishment of this molecular program in nascent neuroectoderm directly links early neural cell fate acquisition with regulatory control of later neurodevelopment.

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Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum

Cited by 146 publications

References 66 publications

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1

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