CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant DOI Creative Commons
Samuel J. Kaplan, Wilfred Wong, Jielin Yan

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114640 - 114640

Published: Aug. 1, 2024

Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among identified, focused on an named ONECUT1e-664kb, ∼664 kb from ONECUT1 promoter. Previous studies have linked coding mutations hypoplasia neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb hPSCs leads near-complete loss expression impaired differentiation. contains type 2 diabetes-associated variant (rs528350911) disrupting GATA motif. Introducing risk into reduced binding key transcription factors (GATA4, GATA6, FOXA2), supporting its causal role This work highlights utility settings monogenic complex disease.

Language: Английский

Gene regulatory network inference in the era of single-cell multi-omics DOI
Pau Badia-i-Mompel, Lorna Wessels, Sophia Müller‐Dott

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(11), P. 739 - 754

Published: June 26, 2023

Language: Английский

Citations

187
Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation DOI
Jin Yang, Anders S. Hansen

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(7), P. 574 - 591

Published: Feb. 27, 2024

Language: Английский

Citations

51
Transformers in single-cell omics: a review and new perspectives DOI
Artur Szałata, Karin Hrovatin,

Sören Becker

et al.

Nature Methods, Journal Year: 2024, Volume and Issue: 21(8), P. 1430 - 1443

Published: Aug. 1, 2024

Language: Английский

Citations

27
Multiplex profiling of developmental cis-regulatory elements with quantitative single-cell expression reporters DOI Creative Commons
Jean‐Benoît Lalanne, Samuel G. Regalado, Silvia Domcke

et al.

Nature Methods, Journal Year: 2024, Volume and Issue: 21(6), P. 983 - 993

Published: May 9, 2024

Abstract The inability to scalably and precisely measure the activity of developmental cis -regulatory elements (CREs) in multicellular systems is a bottleneck genomics. Here we develop dual RNA cassette that decouples detection quantification tasks inherent multiplex single-cell reporter assays. resulting measurement expression accurate over multiple orders magnitude, with precision approaching limit set by Poisson counting noise. Together barcode stabilization via circularization, these scalable quantitative reporters provide high-contrast readouts, analogous classic situ assays but entirely from sequencing. Screening >200 regions accessible chromatin vitro model early mammalian development, identify 13 (8 previously uncharacterized) autonomous cell-type-specific CREs. We further demonstrate chimeric CRE pairs generate cognate two-cell-type profiles assess gain- loss-of-function phenotypes variants perturbed transcription factor binding sites. Single-cell can be applied quantitatively characterize native, synthetic CREs at scale, high sensitivity resolution.

Language: Английский

Citations

18
Current challenges in understanding the role of enhancers in disease DOI
Judith B. Zaugg, Pelin Sahlén, Robin Andersson

et al.

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 29(12), P. 1148 - 1158

Published: Dec. 1, 2022

Language: Английский

Citations

48
Enhancer-gene specificity in development and disease DOI Open Access
Tomás Pachano, Endika Haro, Álvaro Rada-Iglesias

et al.

Development, Journal Year: 2022, Volume and Issue: 149(11)

Published: June 1, 2022

ABSTRACT Enhancers control the establishment of spatiotemporal gene expression patterns throughout development. Over past decade, development new technologies has improved our capacity to link enhancers with their target genes based on colocalization within same topological domains. However, mechanisms that regulate how specifically activate some but not others a given domain remain unclear. In this Review, we discuss recent insights into factors controlling enhancer specificity, including genetic composition and promoters, linear 3D distance between genes, cell-type specific chromatin landscapes. We also elucidating molecular principles specificity might help us better understand predict pathological consequences human genetic, epigenetic structural variants.

Language: Английский

Citations

43
GRaNIE and GRaNPA : inference and evaluation of enhancer‐mediated gene regulatory networks DOI Creative Commons
Aryan Kamal, Christian Arnold, Annique Claringbould

et al.

Molecular Systems Biology, Journal Year: 2023, Volume and Issue: 19(6)

Published: April 19, 2023

Enhancers play a vital role in gene regulation and are critical mediating the impact of noncoding genetic variants associated with complex traits. Enhancer activity is cell-type-specific process regulated by transcription factors (TFs), epigenetic mechanisms variants. Despite strong mechanistic link between TFs enhancers, we currently lack framework for jointly analysing them regulatory networks (GRN). Equally important, an unbiased way assessing biological significance inferred GRNs since no complete ground truth exists. To address these gaps, present GRaNIE (Gene Regulatory Network Inference including Enhancers) GRaNPA Performance Analysis). (https://git.embl.de/grp-zaugg/GRaNIE) builds enhancer-mediated based on covariation chromatin accessibility RNA-seq across samples (e.g. individuals), while (https://git.embl.de/grp-zaugg/GRaNPA) assesses performance predicting differential expression. We demonstrate their power investigating underlying response macrophages to infection, cancer common traits autoimmune diseases. Finally, our methods identify TF PURA as putative regulator pro-inflammatory macrophage polarisation.

Language: Английский

Citations

41
Enhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations DOI Creative Commons

Meyer J. Friedman,

Tobias Wagner, Haram Lee

et al.

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(4), P. 772 - 787

Published: April 25, 2024

Abstract Although often located at a distance from their target gene promoters, enhancers are the primary genomic determinants of temporal and spatial transcriptional specificity in metazoans. Since discovery first enhancer element simian virus 40, there has been substantial interest unraveling mechanism(s) by which communicate with partner promoters to ensure proper expression. These research efforts have benefited considerably application increasingly sophisticated sequencing- imaging-based approaches conjunction innovative (epi)genome-editing technologies; however, despite various proposed models, principles enhancer–promoter interaction still not fully elucidated. In this review, we provide an overview recent progress eukaryotic transcription field pertaining specificity. A better understanding mechanistic basis lineage- context-dependent engagement, along continued identification functional enhancers, will key insights into spatiotemporal control expression that can reveal therapeutic opportunities for range enhancer-related diseases.

Language: Английский

Citations

13
Large language models in bioinformatics: applications and perspectives DOI Creative Commons
Jiajia Liu,

Mengyuan Yang,

Yankai Yu

et al.

arXiv (Cornell University), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Large language models (LLMs) are a class of artificial intelligence based on deep learning, which have great performance in various tasks, especially natural processing (NLP). typically consist neural networks with numerous parameters, trained large amounts unlabeled input using self-supervised or semi-supervised learning. However, their potential for solving bioinformatics problems may even exceed proficiency modeling human language. In this review, we will present summary the prominent used processing, such as BERT and GPT, focus exploring applications at different omics levels bioinformatics, mainly including genomics, transcriptomics, proteomics, drug discovery single cell analysis. Finally, review summarizes prospects bioinformatic problems.

Language: Английский

Citations

10
Rapid and quantitative functional interrogation of human enhancer variant activity in live mice DOI Creative Commons
Ethan W. Hollingsworth, Taryn Audrey Liu, Joshua A. Alcantara

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 6, 2025

Abstract Functional analysis of non-coding variants associated with congenital disorders remains challenging due to the lack efficient in vivo models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison enhancer allele activities live mice less than two weeks. We use this technology examine and measure gain- loss-of-function effects previously linked limb polydactyly, autism spectrum disorder, craniofacial malformation. By combining dual-enSERT single-cell transcriptomics, characterise gene expression cells where is normally ectopically active, revealing candidate pathways that may lead misregulation. Finally, demonstrate widespread utility by testing fifteen uncharacterised rare common neurodevelopmental disorders. In doing so identify reproducibly alter activity OTX2 MIR9-2 brain enhancers, implicating them autism. Dual-enSERT thus allows researchers go from identifying comparative embryos under

Language: Английский

Citations

1