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For the 25th anniversary of Nature Reviews Genetics, we reflect on exciting progress towards decoding the regulatory genome and its mechanisms, a central goal in genetics that must be solved with interdisciplinary research to yield widespread insights into evolution, development and disease.
In this Comment, the authors outline some key next steps to advance our understanding of cis-regulatory elements at single-cell resolution, which includes harmonizing global efforts to construct a comprehensive single-cell atlas of gene regulation.
In this Comment, Wendy Bickmore discusses mechanistic models of how 3D genome organization facilitates communication between distant enhancers and their target promoters to regulate gene expression.
Studies of human regulatory genomics are being performed at biobank scales, with data from tens of thousands of individuals. Stephen Montgomery describes how these datasets will advance our understanding of how variation in gene regulation shapes human traits and disease.
In this Comment, the authors overview the latest deep learning models for predicting regulatory function from genomic sequence and highlight key topics going forward, including the trade-off between specialized and general models, multitasking across cell types, and training on genetic variation and diverse species.
After more than two decades of large-scale efforts to annotate the regulatory genome, Sushant Kumar and Mark Gerstein forecast how new technologies and experimental approaches will pave the way in mapping regulatory elements across cell types, developmental stages and genetically diverse individuals.
In this Tools of the Trade article, Michael Montgomery presents Variant-EFFECTS, a high-throughput and generalizable approach that combines prime editing, flow cytometry, sequencing, and computational analysis to quantify the effects of regulatory variants.
In this Tools of the Trade article, Christina Kajba and Michael Herger describe their screening platform, based on pooled prime editing, for large-scale functional characterization of genetic variants.
In this Journal Club, Juan Fuxman Bass reflects on two papers, by Melnikov et al. and Patwardhan et al., that transformed the field of regulatory genomics by devising methods to study thousands of cis-regulatory elements simultaneously.
Barbadilla-Martínez et al. review recent progress in deep-learning-based sequence-to-expression models, which predict gene expression levels solely from DNA sequence. These models are providing new insights into the complex combinatorial logic underlying cis-regulatory control of gene expression.
Advances in long-read sequencing are driving the implementation of these technologies for transcriptome profiling. The authors provide a comprehensive guide to long-read RNA sequencing, including experimental and computational tools, current applications, challenges and opportunities.
In vivo CRISPR screens generate high-throughput, unbiased genotype–phenotypes maps for complex biological processes that cannot be studied in vitro. This Review outlines key criteria for understanding, designing and implementing such screens and discusses their potential impact on basic and translational research.
Extraordinary advances in genomic science have defined the twenty-first century, transforming our understanding of human biology in both health and disease. This timeline Perspective charts two decades of genomic innovation since the human genome reference sequence became available, highlighting the evolution of sequencing technologies and how they, combined with computational advances, paved the way for genomic medicine.
