Biomedical subjects

Job Dekker

Publications and source records attributed to Job Dekker.

4 recordsLinked to original sources

PubMed2026

Cohesin promotes genomic stability by suppressing unequal sister chromatid exchange.

The protein complex cohesin plays critical roles in genomic stability by tethering together sister chromatids at their pericentric regions and along their arms from S phase until anaphase. Cohesin-mediated pericentric cohesion prevents aneuploidy by ensuring bipolar attachment of sister kinetochores. Arm cohesion prevents loss of heterozygosity by biasing DNA repair via recombination between sister chromatids rather than between homologs. Here, we investigate in yeast whether cohesin also enhances genomic stability by suppressing unequal sister chromatid exchange (USCE) between repetitive sequences. In wild-type cells, the USCE rate between repeats 4kb apart (proximal) was 15X higher than repeats 68kb apart (distal). The USCE between distal repeats but not proximal repeats increased 4 to 7-fold in mutants with altered cohesin subunits or auxiliary factors. The level of increased distal USCE corresponded with reduced arm cohesion, reduced density of cohesion arm sites, and higher sister loci mobility. Our results suggest that high density of arm cohesion sites confines repair of DNA damage to local sequences. When the density of cohesion sites decreases, sister chromatid sequences are less confined, thereby enhancing distal repeat interactions and USCE. Another set of mutations disrupted both DNA replication and cohesin loading at the replication fork during S phase. Remarkably, distal USCE in these mutants increased approximately 100-fold and was 6-fold more likely than proximal USCE. This preferential hyperdistal USCE can be explained by an aberrant sister-chromatid structure that is normally prevented by proper coupling of cohesin function and replication.

Journal Article↗

PubMed2026

UnionLoops: a workflow for calling chromatin loops across related Hi-C datasets with improved specificity, precision, and sensitivity.

Chromatin loop calling from chromatin interaction data often exhibits substantial variability across related samples. We present UnionLoops, a computational workflow for chromatin loop calling across multiple related samples. UnionLoops integrates information across datasets to determine positions and dataset-specificity of looping interactions. It constructs a unified candidate loop set, applies consistent filtering and aggregation, and evaluates loop support across samples. We demonstrate that UnionLoops increases sensitivity for detecting shared chromatin loops, reduces spurious sample-specific calls, and improves concordance with independent genomic features, including CTCF and cohesin occupancy. UnionLoops enables improved biological interpretation of chromatin loop organization and dynamics across related conditions.

Chromatin↗

PubMed2025

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Journal Article↗

PubMed2025

esBAF and INO80C fine-tune subcompartments and differentially regulate enhancer-promoter interactions.

The genome is compacted in the nucleus through a hierarchical chromatin organization, ranging from chromosome territories to compartments, topologically associating domains (TADs), and individual nucleosomes. Nucleosome remodeling complexes hydrolyze ATP to translocate DNA and thereby mobilize histone proteins. While nucleosome remodeling complexes have been extensively studied for their roles in regulating nucleosome positioning and accessibility, their contributions to higher-order chromatin architecture remain less well understood. Here, we investigate the roles of two key nucleosome remodelers, esBAF and INO80C, in shaping 3D genome organization in mouse embryonic stem cells. Using Hi-C, we find that loss of either remodeler has minimal effects on global compartment or TAD structures. In contrast, subcompartment organization is notably altered, suggesting that esBAF and INO80C contribute to finer-scale chromatin topology. To overcome the limited resolution of Hi-C for detecting regulatory loops, we employed promoter capture Micro-C (PCMC), which revealed that the loss of esBAF or INO80C alters a subset of promoter anchored looping interactions. Although these changes occur at distinct genomic loci for each remodeler, the affected sites are commonly enriched for bivalent chromatin regions bound by OCT4, SOX2, and NANOG (OSN), as well as BRG1 and INO80 themselves. Together, our findings reveal that esBAF and INO80C selectively influence subcompartment identity and enhancer-promoter communication at key regulatory loci, highlighting a previously underappreciated role for nucleosome remodelers in higher-order chromatin organization.

chromatin↗