During corticogenesis, neural gene expression is tightly coordinated by chromatin and epigenetic changes, whose misregulation can lead to neurodevelopmental disorders[1][1]–[4][2]. The role of spatial...

Cohesin loop extrusion is a major driver of chromosome folding, but how its dynamics are controlled to shape the genome remains elusive. Here we disentangle the contributions of the cohesin cofactors ...

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...

Genetic variants often produce complex phenotypic effects that confound current assays and predictive models. We developed Variant in situ sequencing (VIS-seq), a pooled, image-based method that measures variant effects on molecular and cellular phenotypes in diverse cell types. Applying VIS-seq to ~3,000 LMNA and PTEN variants yielded high-dimensional morphological profiles that captured variant-driven changes in protein abundance, localization, activity and cell architecture. We identified gain-of-function LMNA variants that reshape the nucleus and autism-associated PTEN variants that mislocalize. Morphological profiles predicted variant pathogenicity with near-perfect accuracy and distinguished autism-linked from tumor syndrome-linked PTEN variants. Most variants impacted a multidimensional continuum of phenotypes not recapitulated by any single functional readout. By linking protein variation to cell images at scale, we illuminate how variant effects cascade from molecular to subcellular to cell morphological phenotypes, providing a framework for resolving the complexity of variant function. ### Competing Interest Statement FPR is an advisor and shareholder in Constantiam Biosciences. National Human Genome Research Institute, https://ror.org/00baak391, RM1HG010461, R01HG013025 National Institute of General Medical Sciences, R35GM152106 National Heart Lung and Blood Institute, https://ror.org/012pb6c26, K99HL177347, R01HL171174, R01HL164675 Chan Zuckerberg Initiative (United States), CZIF2024-010284, CP-2-1-Fowler Brotman Baty Institute, https://ror.org/03jxvbk42, CC28 United States Department of Veterans Affairs, I01BX006428, IK2BX004642 Novo Nordisk Foundation, https://ror.org/04txyc737, Alex's Lemonade Stand for Childhood Cancer RUNX1 Foundation

The REX element is associated with long-range enhancer–promoter interactions.

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...