Biology subjects

Marrero, G.

Publications and source records attributed to Marrero, G..

4 recordsLinked to original sources

bioRxiv2026

Cognitive function depends upon Satb2 gene dosage in cortical projection neurons

SATB2-associated syndrome (SAS) is a severe neurodevelopmental disorder caused by de novo heterozygous SATB2 mutations, yet how haploinsufficiency disrupts brain development remains poorly understood. While homozygous Satb2 loss causes profound embryonic cell-fate defects, we demonstrate using a heterozygous mouse model that SAS phenotypes emerge primarily during postnatal circuit maturation. Integrating chromatin profiling, transcriptomics, electrophysiology, and behavior, we show that SATB2 acts as a dose-sensitive chromatin regulator that binds conserved enhancer-promoter landscapes to orchestrate networks linked to human intelligence. Although excitatory neuron subtype specification is preserved, Satb2 heterozygotes adopt an intermediate epigenetic state that drives cell-type-specific dysregulation of genes enriched for intellectual disability risk variants. Consequently, mutant neurons exhibit simplified dendritic arborization, reduced intrinsic excitability, and weakened layer 2/3-to-layer 5 intracortical connectivity. These circuit deficits culminate in the disorganization of the somatosensory barrel cortex and severe impairments in whisker-dependent texture discrimination. Finally, by restricting Satb2 heterozygosity to the cortex, we decouple these cortical sensory deficits from subcortical vocalization phenotypes. Together, our work links SATB2 dosage to chromatin architecture and postnatal circuit maturation, revealing a critical, post-mitotic therapeutic window for intervention in SAS.

neuroscience↗

bioRxiv2026

In vivo interrogation of transcriptional and epigenetic regulators of lung epithelial regeneration

Effective alveolar repair after viral lung injury requires precise coordination of alveolar type 2 cell (AT2) proliferation and differentiation to restore lung function. To uncover causal regulators of this process in the native tissue environment, we developed SAGE (Stable Adeno-Associated Virus Genomic IntEgration), an engineered AAV system that enables high-throughput in vivo genetic interrogation. SAGE supports both bulk phenotypic screening (SAGE-Perturb) and single-cell transcriptomic profiling (SAGE-Perturb-seq). Using this approach, we identified lysine acetyltransferase 8 (Kat8) as essential for epithelial repair following viral infection through the Non-Specific-Lethal (NSL) complex, and generated a time-resolved, high-resolution functional map of transcription factor knockouts during alveolar repair, revealing transcription factor dependences for distinct alveolar epithelial repair trajectories. This map further defined two independent AT2-derived transitional states: a reparative state, and a pathological state that is transcriptionally similar to the basaloid population observed in human pulmonary fibrosis. Disruption of transcription factors in the NF-{kappa}B pathway prevented the emergence of the pathological transitional state, linking inflammation and maladaptive epithelial remodeling. SAGE represents a versatile platform for functional genomics in vivo, with applications extending across respiratory biology and disease.

genomics↗

bioRxiv2024

Aging disrupts spatiotemporal coordination in the cycling ovary

Throughout the female reproductive lifespan, the ovary completes hundreds of cycles of follicle development, ovulation, and tissue regeneration1-3. These processes rely on the precisely coordinated intricate multicellular interactions across time and space4. How aging disrupts these interactions, leading to an overall decline in reproductive and endocrine functions, remains understudied. To understand the multicellular dynamics that underlie ovarian function and their changes with age, here we use Slide-seq, a near-cellular spatial transcriptomics method, to profile 22 mouse ovaries across the reproductive cycle and chronological age, representing 610,620 near-cellular spots across 69 spatial transcriptomic profiles5,6. We develop a segmentation analysis to identify spatial niches that capture different states of folliculogenesis from static snapshots in situ, allowing us to examine the multicellular dynamics of 358 oocytes, 668 follicles, and 236 corpora lutea. We find that aging disrupts both the spatial organization and temporal coordination of folliculogenesis before the cessation of cycling, which may contribute to the dysregulation of hormone production and signaling. These disruptions are marked by altered immune cell dynamics, inflammatory signaling, and global tissue disorganization that impair the cyclic remodeling required for ovarian function. Our findings reveal how multicellular niches orchestrate ovarian function and demonstrate how age-related breakdown of tissue organization across time and space precedes reproductive decline.

genomics↗

bioRxiv2022

Cortical somatostatin interneuron subtypes form cell-type specific circuits

The cardinal interneuron classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings glosses over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. The organizing principles by which the connectivity of these subtypes is specified are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes. Using these strategies to target three subtypes that span the entire cortical column, we examined their afferent and efferent connectivity. Our data demonstrated that each of these possesses remarkable reciprocal connectivity with the intracortical or corticofugal pyramidal classes, as well as parvalbumin interneurons. Even when two interneuron subtypes shared the same efferent target, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin cortical interneurons form cell-type specific cortical circuits.

neuroscience↗