Biology subjects

Benito, E.

Publications and source records attributed to Benito, E..

4 recordsLinked to original sources

bioRxiv2025

Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Early immune perturbations increase the risk of neurodegenerative and neurodevelopmental disorders, yet the mechanisms underlying the maturation of microglia, the resident immune cells of the brain parenchyma, remain poorly defined. Specifically, how proliferation, morphological differentiation, and phagocytosis are coordinated among microglia progenitors as they colonize the embryonic brain remains unclear. Here, we combined mathematical modeling with spatiotemporal analyses of the murine hippocampus and cerebellum from postnatal day 2 (P2) to P60 to reconstruct the trajectory of microglial development. We identified a proliferative-to-quiescent (P/Q) switch around P3/P4 that preceded the acquisition of morphological complexity and efficient phagocytosis and was accompanied by coordinated shifts in cell-cycle dynamics and metabolic state. Strikingly, this P/Q switch was recapitulated in repopulation contexts in mice and in the human fetal brain, where later stages displayed enhanced phagocytic function coupled to reduced proliferation. Perturbing the proliferative phase through pharmacological or genetic disruption of CSF1R signaling impaired subsequent microglial complexity and phagocytosis efficiency, revealing an unexpected reliance of phagocytosis on proliferation-driven colonization. Finally, we show that microglia stepwise maturation during development is associated with chromatin remodeling and driven by the epigenetic regulator Ikaros. Together, these findings uncover the sequential milestones of microglial development, revealing a potential period of early vulnerability and establishing an unexpected linkage between proliferation and phagocytosis essential to understanding how these processes are coordinated in neurodegenerative disorders.

neuroscience↗

bioRxiv2023

Cell type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells

The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single cell genomes from 19 human donors of increasing age, revealing a heterogeneous mSV landscape in hematopoietic stem and progenitor cells (HSPCs). While mSV clonal expansions are confined to individuals over 60, de novo mSV formation occurs consistently across age, frequently leading to megabase-scale segmental aneuploidies. Cells harboring subclonal mosaicism show evidence for increased mSV formation. To enable high-resolution cell-typing of each Strand-seq library, we generated single-cell MNase-seq reference datasets for eight distinct HSPCs. Subclonal mSVs frequently exhibit enrichment in myeloid progenitors, and single-cell multiomic analysis suggests that these mSVs result in recurrent dysregulation of pathways related to proliferation and metabolism, including Ras signaling and lipid metabolism. The comprehensive mSV landscape identified in this study implicates mSVs in cell type-specific molecular phenotypes, establishing a foundation for deciphering links between mSVs, aging, and disease risk.

genomics↗

bioRxiv2021

Haplotype-resolved inversion landscape reveals hotspots of mutational recurrence associated with genomic disorders

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1-retrotransposition; 80% of the larger inversions are balanced and affect twice as many base pairs as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or mobile elements. Since this suggests recurrence due to non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7x10-4 per locus and generation. Recurrent inversions exhibit a sex- chromosomal bias, and significantly co-localize to the critical regions of genomic disorders. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes to disease- causing CNVs.

genomics↗

bioRxiv2017

RNA-dependent intergenerational inheritance of enhanced synaptic plasticity after environmental enrichment

Physical exercise in combination with cognitive training is known to enhance synaptic plasticity and lower the risk for various complex diseases including Alzheimers disease. Here we show that exposure of adult male mice to an environmental enrichment paradigm leads to long-lasting enhancement of synaptic plasticity that is also passed on to the next generation. We show that the effect is mediated through sperm RNA and is explained by microRNAs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific microRNAs as candidates mechanistically involved in this type of transmission.

neuroscience↗