Long-range enhancer-controlled genes are hypersensitive to regulatory factor perturbations

Cell Genomics, Journal Year: 2025, Volume and Issue: unknown, P. 100778 - 100778

Published: Feb. 1, 2025

Cell-type-specific gene activation is regulated by enhancers, sometimes located at large genomic distances from target promoters. Whether distal enhancers require specific factors to orchestrate regulation remains unclear. Here, we used enhancer distance-controlled reporter screens find candidate factors. We depleted them and employed activity-by-contact predictions genome-wide classify genes based on distance. Predicted typically control tissue-restricted often are strong enhancers. cohesin, but also mediator, most specifically required for long-range activation, with cohesin repressing short-range prioritizing over proximal HBB competing shared Long-range controlled sensitive perturbations of other regulatory proteins BET inhibitor JQ1, this being more a consequence their distinct features than Our work predicts that lengthening intervening sequences can help limit the expression specialized cells optimal trans-factor environments.

Language: Английский

---

Bridging the gap: How enhancers cooperate to regulate gene expression over large genomic distances

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 199 - 201

Published: Jan. 1, 2025

Language: Английский

---

Bridging spatial and temporal scales of developmental gene regulation

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102328 - 102328

Published: March 12, 2025

The development of multicellular organisms relies on the precise coordination molecular events across multiple spatial and temporal scales. Understanding how information flows from interactions to cellular processes tissue organization during is crucial for explaining remarkable reproducibility complex organisms. This review explores chromatin-encoded transduced localized transcriptional global gene expression patterns, highlighting challenge bridging these We discuss recent experimental findings theoretical frameworks, emphasizing polymer physics as a tool describing relationship between chromatin structure dynamics By integrating perspectives, we aim clarify regulation coordinated levels biological suggest strategies future approaches.

Language: Английский

---

Modelling and design of transcriptional enhancers

Nature Reviews Bioengineering, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Language: Английский

---

Enhancer control of promoter activity and variabilityviafrequency modulation of clustered transcriptional bursts

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 29, 2025

Abstract Gene expression in mammalian cells is controlled by enhancers that are often dispersed across large cis -regulatory landscapes around a promoter. Yet how determine transcription of their target genes, and this depends on relative position inside landscape remains unclear. Here we use live-cell imaging to track the activity promoter under control same enhancer, but inserted at different positions simplified regulatory with minimal complexity. Combined mathematical modeling, reveals RNA production from occurs clusters transcriptional bursts, enhancer controlling frequency which such appear. This results bursts being more frequent occurring uniformly when genomically close than it located genomic distance. Mathematical modeling further indicates modulates promoter’s ability transition its basal state regime where become frequent. Our challenge existing models operation, reveal within critically controls timing variability output single cells.

Language: Английский

---

Is Enhancer Function Driven by Protein–Protein Interactions? From Bacteria to Leukemia

BioEssays, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

ABSTRACT The precise regulation of the transcription genes is essential for normal development and maintenance life. Aberrant gene expression changes drive many human diseases. Despite this, we still do not completely understand how controlled in living systems. Enhancers are key regulatory elements that enable cells to specifically activate response environmental cues, or a stage tissue‐specific manner. Any model enhancer activity needs answer two main questions: (1) enhancers able identify act on specific (2) influence transcription. To address these points, first outline some basic principles can be established from simpler prokaryotic systems, then discuss recent work aberrant leukemia. We argue highly protein–protein interactions driver enhancer‐promoter proximity, allowing enhancer‐bound factors directly RNA polymerase

Language: Английский

---

Cis-Regulation of the CFTR Gene in Pancreatic Cells

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3788 - 3788

Published: April 17, 2025

Genome organization is essential for precise spatial and temporal gene expression relies on interactions between promoters distal cis-regulatory elements (CREs), which constitute ~8% of the human genome. For cystic fibrosis transmembrane conductance regulator (CFTR) gene, tissue-specific expression, especially in pancreas, remains poorly understood. Unraveling its regulation could clarify clinical heterogeneity observed CFTR-related disorders. To understand role 3D chromatin architecture establishing CFTR we mapped epigenomic Capan-1 pancreatic cells. Candidate CREs are validated by luciferase reporter assay CRISPR knock-out. We identified active not only around but also outside topologically associating domain (TAD). demonstrate involvement multiple upstream downstream reveal a cooperative effect −44 kb, −35 +15.6 +37.7 kb regions, share common predicted transcription factor (TF) motifs. extend our analysis to compare conformation intestinal cells, providing valuable insights into tissue specificity regulating expression.

Language: Английский

---

Genetic factors mediating long-range enhancer–promoter communication in mammalian development

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 90, P. 102282 - 102282

Published: Nov. 22, 2024

Language: Английский

---