Type 2 diabetes (T2D) arises from genetic susceptibility and chronic metabolic stress, but whether these converge on shared molecular programs in human populations remains unclear. Here, we develop a ...

This study contributes a resource of predicted effects of noncoding variants on chromatin accessibility and a method to identify noncoding variants with extreme regulatory effects, with application to...

Expression quantitative trait locus (eQTL) studies in human cohorts typically detect at least one regulatory signal per gene, and have been proposed as a way to explain mechanisms of genetic liability...

Background The emergence of genomic language models (gLMs) offers an unsupervised approach to learning a wide diversity of cis-regulatory patterns in the non-coding genome without requiring labels of ...

Messenger RNA (mRNA) is central in gene expression, and its half-life, localization, and translation efficiency drive phenotypic diversity in eukaryotic cells. While supervised learning has widely bee...

Kefalopoulou, Rullens et al. develop Dam&ChIC to assay chromatin state at two different time points in the same cell. The method was used to study the reorganization of LADs during cell division a...

The HLA region plays an important role in human health but is often excluded in large-scale GWASs. We performed haplotype-based associations from genotype data to investigate pleiotropy across thousan...

Activation of an LTR retrotransposon inserted upstream of the Fgf8 gene produces viral-like particles in the mouse developing limb, triggering apoptosis and causing limb malformation. This phenotype c...

Most genetic variants associated with complex diseases lie in non-coding regions, complicating efforts to identify effector genes and relevant cell types. Here, we map cis-eQTLs across 2.2 million sin...

More than 2,700 human mRNA 3′UTRs have hundreds of highly conserved (HC) nucleotides, but their biological roles are unclear. Here, we show that mRNAs with HC 3′UTRs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. These proteins are only fully active when translated from mRNA templates that include their 3′UTRs, raising the possibility of functional interactions between 3′UTRs and IDRs. Rather than affecting protein abundance or localization, we find that HC 3′UTRs control transcriptional or histone demethylase activity through co-translationally determined protein oligomerization states that are kinetically stable. 3′UTR-dependent changes in protein folding require mRNA-IDR interactions, suggesting that mRNAs act as IDR chaperones. These mRNAs are multivalent, a biophysical RNA feature that enables their translation in network-like condensates, which provide favorable folding environments for proteins with long IDRs. These data indicate that the coding sequence is insufficient for the biogenesis of biologically active conformations of IDR-containing proteins and that RNA can catalyze protein folding. ### Competing Interest Statement The authors have declared no competing interest. Pershing Square Foundation, https://ror.org/04tce9s05 G. Harold & Leila Y. Mathers Foundation National Institutes of Health, DP1GM123454, R35GM144046 Memorial Sloan Kettering Cancer Center, https://ror.org/02yrq0923, P30 CA008748

Long-read sequencing (LRS) has revealed a far greater diversity of RNA isoforms than earlier technologies, increasing the critical need to determine which, and how many, isoforms per gene are biologic...

The placenta plays a critical role in fetal development and mediates maternal metabolic effects on offspring health outcomes. Despite its importance, the placenta remains understudied in large-scale g...

Huangfu and colleagues identified two NANOG enhancers from a CRISPR interference (CRISPRi) screen in hESCs. Heterozygous deletions of either enhancer significantly lowered NANOG expression, reduced hE...

HARE5, a human accelerated region enhancer, modulates cortical development by influencing neural progenitor cell behaviour, leading to an enlarged neocortex with increased functional independence betw...

Abstract. Predicting how genetic variation affects phenotypic outcomes at the organismal, cellular, and molecular levels requires deciphering the cis-regul

Tissue-resident macrophages (TRMs) are innate immune cells that participate in tissue development, homeostasis, and immune surveillance. Extensive efforts have been made to recapitulate TRM developmen...

Single-cell omics methods promise to revolutionize our understanding of gene regulatory processes during cell differentiation, but analysis of such data continues to pose a major challenge. Apart from...

Diverse forms of heterochromatin block inappropriate transcription and safeguard differentiation and cell identity. Yet, how and when heterochromatin is reconfigured to facilitate changes in cell-fate...

Here, the authors develop a high-throughput assay to measure the jumping potential of thousands of transposons in parallel.

Transcription factors (TFs) establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility, and regulating gene expre...

The development of modern genome editing tools has enabled researchers to make such edits with high precision but has left unsolved the problem of designing these edits. As a solution, we propose Ledi...

Determining genetic variant effects on molecular phenotypes like gene expression is a task of paramount importance to medical genetics. DNA convolutional neural networks (CNNs) attain state-of-the-art...

Pluripotent stem cells are susceptible to acquiring detrimental epigenetic abnormalities, posing a hurdle to their safe use in biomedical applications. Using pluripotent cells with defined genetic backgrounds, Stadtfeld and colleagues show that genetic variation is a major driver of epigenome stability and identify candidate regulators. These findings will enable novel approaches to stabilize the epigenome of pluripotent cells in culture.

Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS has revealed the non-coding genome as a significant contributor to disease. However, prioritizing causal...

A longstanding barrier in genome engineering with CRISPR-Cas9 has been the inability to measure Cas9 edit outcomes and their functional effects at single-cell resolution. Here we present Superb-seq , ...

A major focus of human genetics is to map severe disease mutations. Increasingly that goal is understood as requiring huge numbers of people to be sequenced from every broadly-defined genetic ancestry...

Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) ...

We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into re...