Biology subjects

Espeso-Gil, S.

Publications and source records attributed to Espeso-Gil, S..

4 recordsLinked to original sources

bioRxiv2023

R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription

Here, we construct genome-scale maps for R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in the proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix, with preferential formation at promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations and defective functional and structural neuronal connectivity in vivo and in vitro. Therefore, R- loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells.

genomics↗

bioRxiv2022

SATB2 organizes the 3D genome architecture of cognition in cortical neurons

SATB2 is genetically associated with human intelligence. Since SATB2 protein structure predicts a function in DNA looping, we analyzed the impact of SATB2 on 3D genome architecture and chromatin accessibility in cortical neurons. Our data reveal strong effects of SATB2 on chromatin looping between enhancers and promoters of neuronal activity-regulated genes, which closely correlate with gene expression. We furthermore identify SATB2-dependent alterations at all 3D genome architectural levels, including compartments, Topologically Associated Domains and Frequently Interacting Regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. The altered non-coding regions are enriched for common variants associated with educational attainment, intelligence and schizophrenia. Our data establish SATB2 as a 3D genome organizer, which operates both independently and in cooperation with CTCF to set up the chromatin landscape of pyramidal neurons for cognitive processes.

neuroscience↗

bioRxiv2021

NEURON-SPECIFIC CHROMOSOMAL MEGADOMAIN ORGANIZATION IS ADAPTIVE TO RECENT RETROTRANSPOSON EXPANSIONS

Here, we mapped cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Comparative chromosomal conformation mapping in Mus spretus and Mus musculus revealed neuron-specific reconfigurations tracking recent ERV2 retrotransposon expansions in the murine germline, with significantly higher B2 megadomain contact frequencies at sites with ongoing ERV2 insertions in Mus musculus. Ablation of the retrotransposon silencer Kmt1e/Setdb1 triggered B2 megadomain disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly of ERV2/Intracisternal-A-Particles (IAPs) infiltrating dendrites and spines. We conclude that neuronal megadomain architectures include evolutionarily adaptive heterochromatic organization which, upon perturbation, unleashes ERV proviruses with strong tropism within mature neurons.

neuroscience↗

bioRxiv2021

Environmental enrichment induces epigenomic and genome organization changes relevant for cognitive function

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization. Highlights- Environmental enrichment (EE) alters chromatin conformation, CTCF binding, and spatially 3D genome changes, thereby regulating cognitive function during the first steps of life after birth. - Transcription-associated gene body marks H3K79me2 and H3K36me3 are differently influenced by EE in cortical brain cells and binding is exacerbated upon stimulation in an age-dependent manner. - EE-induced changes of 3D genome organization increase inter-chromosomal interactions of genes associated with synaptic transmission and AMPA receptor genes on chromosomes 7 and 17.

neuroscience↗