Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation

Brennan, Kaelan J.; Weilert, Melanie; Krueger, Sabrina; Pampari, Anusri; Liu, Hsiao-Yun; Yang, Ally; Morrison, Jason A.; Hughes, Timothy R.; Rushlow, Christine; Kundaje, Anshul; Zeitlinger, Julia

doi:10.1016/j.devcel.2023.07.007

Cited by 10 publications

(14 citation statements)

References 164 publications

(280 reference statements)

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“…This variant is directly within ONECUT1e-664kb and is highly confidently fine-mapped with the posterior probability of association (PPA) close to 1 (0.994) 27 . To predict if rs528350911 would affect enhancer activation in pancreatic development, we trained a ChromBPNet 78,79 model on PFG-stage ATAC-seq data 25 . Then, we computed per nucleotide DeepLift 80 attribution scores across the region for both the reference and alternate sequences of rs528350911.…”

Section: Resultsmentioning

confidence: 99%

CRISPR Screening Uncovers a Long-Range Enhancer forONECUT1in Pancreatic Differentiation and Links a Diabetes Risk Variant

Kaplan,

Wong,

Yan

et al. 2024

Preprint

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Functional enhancer annotation is a valuable first step for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants for investigation. However, unbiased enhancer discovery in physiologically relevant contexts remains a major challenge. To discover regulatory elements pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers uncovered, we focused on a long-range enhancer ~664 kb from the ONECUT1 promoter, as coding mutations in ONECUT1 cause pancreatic hypoplasia and neonatal diabetes. Homozygous enhancer deletion in hPSCs was associated with a near-complete loss of ONECUT1 gene expression and compromised pancreatic differentiation. This enhancer contains a confidently fine-mapped type 2 diabetes (T2D) associated variant (rs528350911) which disrupts a GATA motif. Introduction of the risk variant into hPSCs revealed substantially reduced binding of key pancreatic transcription factors (GATA4, GATA6 and FOXA2) on the edited allele, accompanied by a slight reduction of ONECUT1 transcription, supporting a causal role for this risk variant in metabolic disease. This work expands our knowledge about transcriptional regulation in pancreatic development through the characterization of a long-range enhancer and highlights the utility of enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

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Section: Resultsmentioning

confidence: 99%

CRISPR Screening Uncovers a Long-Range Enhancer forONECUT1in Pancreatic Differentiation and Links a Diabetes Risk Variant

Kaplan,

Wong,

Yan

et al. 2024

Preprint

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“…Indeed, the optimal spacing of the Tead double motif is not found more frequently than other spacings in the genome, e.g., a relative spacing of +2 bp is more frequent (Figure 4B). Moreover, BPNet has been shown to learn relative motif affinities 17,20,23,101 and thus might be adept at learning degenerate versions of a motif.…”

Section: Resultsmentioning

confidence: 99%

“…The key step is then to interrogate the model and extract the learned sequence rules using interpretation tools 15 . This reveals the learned TF motifs, including measurements of their relative affinities and the syntax rules, thus the distance relationships by which motifs cooperate with each other 15,17,20,22,23 .…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, strictly spaced motifs are not frequently observed in the genome, raising the question of whether TF binding cooperativity may also occur through more flexible motif syntax 27–29 . For example, we previously found that a TF may enhance the binding of another TF through soft motif syntax, which occurs at variable motif distances within ∼150 bp but is stronger at closer distances 15,20 .…”

Section: Introductionmentioning

confidence: 99%

“…To discover these potential sequence rules, we performed the TF binding experiments at the highest resolution and leveraged our previously developed deep learning model BPNet to predict the data at base resolution from genomic sequences of 1-kb 15,20,22,37,38 . This approach optimally resolves sequence rules between closely spaced motifs within enhancers 15 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interpretable deep learning reveals the sequence rules of Hippo signaling

Dalal,

McAnany,

Weilert

et al. 2024

Preprint

Self Cite

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SummaryThe response to signaling pathways is highly context-specific, and identifying the transcription factors and mechanisms that are responsible is very challenging. Using the Hippo pathway in mouse trophoblast stem cells as a model, we show here that this information is encoded incis-regulatory sequences and can be learned from high-resolution binding data of signaling transcription factors. Using interpretable deep learning, we show that the binding levels of TEAD4 and YAP1 are enhanced in a distance-dependent manner by cell type-specific transcription factors, including TFAP2C. We also discovered that strictly spacedTead doublemotifs are widespread highly active canonical response elements that mediate cooperativity by promoting labile TEAD4 protein-protein interactions on DNA. These syntax rules and mechanisms apply genome-wide and allow us to predict how small sequence changes alter the activity of enhancersin vivo. This illustrates the power of interpretable deep learning to decode canonical and cell type-specific sequence rules of signaling pathways.Graphical abstract

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Pioneer factors: roles and their regulation in development

Barral,

Zaret

2024

Trends in Genetics

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Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation

Cited by 10 publications

References 164 publications

CRISPR Screening Uncovers a Long-Range Enhancer forONECUT1in Pancreatic Differentiation and Links a Diabetes Risk Variant

CRISPR Screening Uncovers a Long-Range Enhancer forONECUT1in Pancreatic Differentiation and Links a Diabetes Risk Variant

Interpretable deep learning reveals the sequence rules of Hippo signaling

Pioneer factors: roles and their regulation in development

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