Gene regulatory changes are considered major drivers of evolutionary innovations, including the cerebellum’s expansion during human evolution, yet they remain largely unexplored. In this study, we com...

Using a combination of microglia-specific conditional mouse knockout and knockin approaches and xenotransplantation of human iPSC-derived microglia, Diaz-Salazar et al. demonstrate that the human-spec...

The roles of transposable elements in primate brain development remain underexplored. Here, the authors identify transposable elements with ancestral regulatory potential that have been co-opted as ci...

Generating high-quality training data for machine learning is costly. Here, authors include sequence-to-function modeling in benchmarking of custom and commercial droplet-based scATAC platforms, and r...

This study introduces Corgi and Corgi+ , biology-inspired deep neural network models of regulatory DNA sequences that can generalize to unseen cell types. They accurately impute epigenomic d...

Neural crest evolution reassembled ancient programs in pigment cell lineage, resulting in vertebrate innovations.

The genetic program of animal development is conserved, but its rate of execution varies across species. Heterochrony, shifts in the relative timing of developmental events, generates phenotypic varia...

The updated OrthoFinder v3 software boosts accuracy and scalability in phylogenetic orthology inference with massive and diverse datasets.

Complete, haplotype-resolved genome assemblies have provided unprecedented insight into the evolution of structurally complex, rapidly evolving regions of human genomes; however, population-scale pang...

Cell viability depends on the precise expression of essential genes, which are controlled by CpG-island (CGI) promoters densely bound by transcription factors (TFs). This has led to the prevailing model that TFs cooperate to ensure ubiquitous expression. Here, using rapid and reversible single and combinatorial degradation in murine stem cells, we systematically dissect the regulatory interactions between five key TFs. We uncover an unexpectedly specific architecture in which regulatory dominance, rather than cooperation, is the prevailing mode, where individual TFs autonomously drive chromatin opening and gene activation at largely distinct promoters. Cooperative regulation occurs at a minority of sites with antagonistic or synergistic outcomes modulated by the interplay between nucleosome positioning and TF sensitivity to chromatin. This logic is recapitulated at synthetic sequences and reflected in human genetic variation. These findings reveal that single TFs dominantly activate distinct sets of CGI-linked genes, including essential genes, across development, homeostasis, and disease. ### Competing Interest Statement The authors have declared no competing interest. DFG, GR 6341/2-1, 556634773

Over the past decade, the rapid expansion of large-scale data and advances in computational power have allowed machine learning (ML), especially deep …

Gene expression is governed by the DNA sequence, which is read out through complex interactions between transcription factors (TFs), co-activators, and chromatin. Massively Parallel Reporter Assays (MPRAs) provide a high-throughput framework for functionally characterizing how regulatory DNA sequences impact the expression of a model gene. MPRAs have also proven to be useful for measuring the effects of genetic variation, where each allele is typically tested in the center of ~200 bp of genomic context cloned into the MPRA, but the impact of variant position and local context remains largely unexplored. In this study, we systematically investigate how shifting the position of a variant within an MPRA probe influences its regulatory activity using models that predict expression in MPRAs from DNA sequence. We find that while the direction of variant effects is usually preserved across positions, the magnitude of expression changes can vary substantially depending on where the variant is placed within the construct. This positional bias appears to be largely explained by the strong position-dependent activity of TFs whose binding the variants perturb. In a subset of cases, interactions consistent with cooperativity between TFs also contribute to position-specific effects. ~1% of variants appear to disrupt RNA polymerase III (Pol III) promoters within Alu elements, resulting in position-specificity because both A and B boxes are required for function and exclusion of either motif due to window shifts disrupts the variants' effects. However, we saw little evidence to support the hypothesis that the positional dependence of variant effects resulted from the redundancy of motifs. Overall, our study demonstrates the complexity of cis-regulatory grammar and how it can confound the interpretation of regulatory variants. ### Competing Interest Statement R.T. has filed intellectual property related to MPRA and MPRA models. The other authors declare no competing interests.

Nature Reviews Genetics - In this Perspective, Maizels and Briscoe discuss the limitations of current models of gene regulatory networks and outline solutions to harness data abundance without...

This Perspective explores the co-evolution of transposable elements and KRAB zinc-finger proteins in relation to their integration into human gene regulatory networks, highlighting their potential eff...

High-sugar diets cause human metabolic diseases, yet several bird lineages convergently adapted to feeding on sugar-rich nectar or fruits. We investigated the underlying molecular mechanisms in hummin...

Nature Ecology & Evolution - This Review discusses recent advances in the molecular evolution of vertebrate organs, including rates of evolution of organs and cell types, molecular mechanisms...