Biology subjects

Alcoverro-Bertran, M.

Publications and source records attributed to Alcoverro-Bertran, M..

2 recordsLinked to original sources

bioRxiv2024

Synergistic and antagonistic activities of IRF8 and FOS enhancer pairs during an immune cell fate switch

Cell-fate instructive genes tend to be regulated by large clusters of enhancers. Whether and how individual enhancers within such clusters cooperate in regulating gene expression is poorly understood. We have previously developed a computational method, SEGCOND, that identifies hubs consisting of enhancer clusters and their target genes, termed Putative Transcriptional Condensates (PTCs). Using SEGCOND, we identified PTCs in a CEBPA-induced B-cell to macrophage transdifferentiation system. We found them to be enriched for highly expressed, lineage-restricted genes and to associate with BRD4, a component of transcriptional condensates. Here we performed single and combinatorial deletions of enhancers within two active PTCs after transdifferentiation is induced, harboring IRF8 and FOS. Two enhancers within the IRF8 PTC were found to form a backup mechanism when combined, safeguarding IRF8 expression and transdifferentiation kinetics. Unexpectedly, two individual enhancers within the FOS PTC antagonize each other at Day 1 of transdifferentiation, delaying the conversion of B-cells to macrophages and reducing FOS expression, but cooperate to increase FOS levels in Day 7 induced cells. Our results reveal differentiation stage-specific, complex interactions, between individual enhancers within a cluster.

genomics↗

bioRxiv2023

SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state

Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. By profiling the chromatin-bound proteome (chromatome) through genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos leads to developmental arrest, reduction of H3K9me3, and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.

developmental biology↗