ChromBPNet: bias factorized, base-resolution deep learning models of chromatin accessibility reveal cis-regulatory sequence syntax, transcription factor footprints and regulatory variants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 25, 2024

Despite extensive mapping of cis-regulatory elements (cREs) across cellular contexts with chromatin accessibility assays, the sequence syntax and genetic variants that regulate transcription factor (TF) binding at context-specific cREs remain elusive. We introduce ChromBPNet, a deep learning DNA model base-resolution profiles detects, learns deconvolves assay-specific enzyme biases from regulatory determinants accessibility, enabling robust discovery compact TF motif lexicons, cooperative precision footprints assays sequencing depths. Extensive benchmarks show despite its lightweight design, is competitive much larger contemporary models predicting variant effects on pioneer reporter activity cell ancestry, while providing interpretation disrupted syntax. ChromBPNet also helps prioritize interpret influence complex traits rare diseases, thereby powerful lens to decode variation.

Язык: Английский

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CRISPR-Based Regulation for High-Throughput Screening

ACS Synthetic Biology, Год журнала: 2025, Номер unknown

Опубликована: Май 22, 2025

CRISPR technology has revolutionized genome editing by enabling precise, permanent modifications to genetic material. To circumvent the irreversible alterations associated with traditional methods and facilitate research on both essential nonessential genes, interference or inhibition (CRISPRi) activation (CRISPRa) were developed. The gene-silencing approach leverages an inactivated Cas effector protein paired guide RNA obstruct transcription initiation elongation, while gene-activation exploits programmability of activate gene expression. Recent advances in CRISPRi technology, combination other technologies (e.g., biosensing, sequencing), have significantly expanded its applications, allowing for genome-wide high-throughput screening (HTS) identify determinants phenotypes. These strategies been applied biomedicine, industry, basic research. This review explores regulation mechanisms, offers overview workflow CRISPR-based screens, highlights superior suitability HTS across biomedical industrial applications. Finally, we discuss limitations current CRISPRi/a envision future directions CRISPR-mediated research, considering potential broader application diverse fields.

Язык: Английский

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Discovery of NANOG enhancers and their essential roles in self-renewal and differentiation in human embryonic stem cells

Stem Cell Reports, Год журнала: 2025, Номер unknown, С. 102511 - 102511

Опубликована: Май 1, 2025

Язык: Английский

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A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes

Cell Reports, Год журнала: 2024, Номер 43(11), С. 114853 - 114853

Опубликована: Окт. 19, 2024

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A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

In a patient with permanent neonatal syndromic diabetes clinically similar to cases ONECUT1 biallelic mutations, we identified disease-causing deletion located upstream of ONECUT1. Through genetic, genomic and functional studies crucial regulatory region acting as an enhancer specifically during pancreatic development. This contains low-frequency variant showing strong association type 2 other glycemic traits, thus extending the contribution this common forms diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying coding or mutations.

Язык: Английский

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CUTting through the distance: A disease-relevant long-range ONECUT1 enhancer

Cell Reports, Год журнала: 2024, Номер 43(11), С. 114897 - 114897

Опубликована: Окт. 19, 2024

Язык: Английский

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