NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program

Pataskar, Abhijeet; Jung, Johannes; Smialowski, Pawel; Noack, Florian; Calegari, Federico; Straub, Tobias; Tiwari, Vijay

doi:10.15252/embj.201591206

Cited by 242 publications

(247 citation statements)

References 72 publications

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“…Changes in the epigenetic landscape after transcription factor binding was also observed for the doxycycline-mediated induction of the basic helix-loop-helix protein NeuroD1 in murine embryonic stem cells (Pataskar et al 2016). Induced NeuroD1 binding to specific target enhancers results in a subsequent loss of repressive H3K27me3 marks and a gain of H3K27ac marks and target gene expression.…”

Section: Discussionmentioning

confidence: 81%

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

et al. 2018

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B-cell fate determination requires the action of transcription factors that operate in a regulatory network to activate B-lineage genes and repress lineage-inappropriate genes. However, the dynamics and hierarchy of events in B-cell programming remain obscure. To uncouple the dynamics of transcription factor expression from functional consequences, we generated induction systems in developmentally arrested Ebf1 −/− pre-pro-B cells to allow precise experimental control of EBF1 expression in the genomic context of progenitor cells. Consistent with the described role of EBF1 as a pioneer transcription factor, we show in a time-resolved analysis that EBF1 occupancy coincides with EBF1 expression and precedes the formation of chromatin accessibility. We observed dynamic patterns of EBF1 target gene expression and sequential up-regulation of transcription factors that expand the regulatory network at the pro-B-cell stage. A continuous EBF1 function was found to be required for Cd79a promoter activity and for the maintenance of an accessible chromatin domain that is permissive for binding of other transcription factors. Notably, transient EBF1 occupancy was detected at lineage-inappropriate genes prior to their silencing in pro-B cells. Thus, persistent and transient functions of EBF1 allow for an ordered sequence of epigenetic and transcriptional events in B-cell programming.

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Section: Discussionmentioning

confidence: 81%

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

et al. 2018

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“…As they represent direct downstream targets of NEUROG2 and SOX4, ChIP for NEUROD1 and NEUROD4 was used to investigate the occupancy of these factors within regions of newly open chromatin (Figure 4F). Publicly available ChIP-seq datasets from mouse cortical tissue were analyzed for potential target sites that directly overlap with human NEUROG2 ChIP and ATAC-seq sites (Pataskar et al., 2016). NEUROD1 was enriched at NEUROG2 bound sites in regions of DLL3 , HES6 , and NHLH1 , while NEUROD4 was significantly less enriched within these loci in reprogrammed human fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming

et al. 2016

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SummaryPro-neural transcription factors and small molecules can induce the reprogramming of fibroblasts into functional neurons; however, the immediate-early molecular events that catalyze this conversion have not been well defined. We previously demonstrated that neurogenin 2 (NEUROG2), forskolin (F), and dorsomorphin (D) can reprogram fibroblasts into functional neurons with high efficiency. Here, we used this model to define the genetic and epigenetic events that initiate an acquisition of neuronal identity. We demonstrate that NEUROG2 is a pioneer factor, FD enhances chromatin accessibility and H3K27 acetylation, and synergistic transcription activated by these factors is essential to successful reprogramming. CREB1 promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma cell and skin fibroblast reprogramming can be improved using SOX4 or chromatin-modifying chemicals.

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“…It will be interesting to further investigate the nature of the complex as we noticed that the AMS variant introduces a change of one nucleotide in the conserved binding motif recognized by NEUROD1 (S3 Fig). This transcription factor plays an important role during the neurogenesis by binding to regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms [65]. In this context, decreased binding of neurogenic transcription factors to the mutated enhancer in dog could explain the weak expression of GDNF / GDNF-AS partnership in neuropathies.…”

Section: Discussionmentioning

confidence: 99%

A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies

Plassais¹,

Lagoutte²,

Correard³

et al. 2016

PLoS Genet

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Human Hereditary Sensory Autonomic Neuropathies (HSANs) are characterized by insensitivity to pain, sometimes combined with self-mutilation. Strikingly, several sporting dog breeds are particularly affected by such neuropathies. Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact. Through a Genome Wide Association Study (GWAS) with 24 affected and 30 unaffected sporting dogs using the Canine HD 170K SNP array (Illumina), we identified a 1.8 Mb homozygous locus on canine chromosome 4 (adj. p-val = 2.5x10-6). Targeted high-throughput sequencing of this locus in 4 affected and 4 unaffected dogs identified 478 variants. Only one variant perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in a long intergenic non-coding RNAs (lincRNA), GDNF-AS. Using human comparative genomic analysis, we observed that the canine variant maps onto an enhancer element. Quantitative RT-PCR of dorsal root ganglia RNAs of affected dogs showed a significant decrease of both GDNF mRNA and GDNF-AS expression levels (respectively 60% and 80%), as compared to unaffected dogs. We thus performed gel shift assays (EMSA) that reveal that the canine variant significantly alters the binding of regulatory elements. Altogether, these results allowed the identification in dogs of GDNF as a relevant candidate for human HSAN and insensitivity to pain, but also shed light on the regulation of GDNF transcription. Finally, such results allow proposing these sporting dog breeds as natural models for clinical trials with a double benefit for human and veterinary medicine.

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NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program

Cited by 242 publications

References 72 publications

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming

A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies

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