Biology subjects

DeBerardine, M.

Publications and source records attributed to DeBerardine, M..

8 recordsLinked to original sources

bioRxiv2026

PIANO: Probabilistic Inference Autoencoder Networks for multi-Omics enables robust generative modeling of gene expression and scales single-cell integration to 100 million cells

Single-cell RNA technologies enable the routine acquisition of transcriptomic atlases. However, these molecular profiles are influenced by overlapping sources of variation. Since these covariates confound comparisons, data integration is the first step in most analyses. Three challenges remain: correcting strong batch effects, scaling to millions of cells, and modeling how covariates influence gene expression. To address these challenges, we developed PIANO: Probabilistic Inference Autoencoder Networks for multi-Omics, a deep learning framework whose central feature is a generative model of gene expression data. Additionally, PIANO achieves robust integrations and trains 10x faster than previous methods. PIANO accurately integrates single-cell data across species and across single-cell and spatial transcriptomics modalities. As practical applications, PIANO models spatially-resolved gene expression during Alzheimer's disease progression in human brains and integrates over 100 million cancer cells to model drug perturbations. In summary, PIANO's integration and generative modeling capabilities will empower novel insights for countless future studies.

bioinformatics↗

bioRxiv2025

Cross-species consensus atlas of the primate basal ganglia

The basal ganglia (BG) are conserved brain regions essential for motor control, learning, emotion, and cognition, and are implicated in neurological and psychiatric disease. Yet a unified cross-species taxonomy of BG cell types is lacking, limiting translation of BG circuit mechanisms, interpretation of human genetic risk, and development of cell type-targeted tools. We present a multiomic consensus atlas of 1.8 million nuclei from human, macaque, and marmoset spanning eight BG structures. Integrating cross-species gene expression, open chromatin, and spatial profiling enables definition of conserved and divergent cell types. Alignment to existing mouse and human atlases identifies 61 homologous cell types conserved over 80 million years. We identify a STRd D2 StrioMat Hybrid medium spiny neuron (MSN) type with molecular, electrophysiological, and morphological features that clarify hybrid MSN identities. Comparative cis-regulatory analysis reveals conserved sequence grammars that encode cell identity and inform viral targeting strategies, providing a foundational resource for BG evolution, function, and disease.

neuroscience↗

bioRxiv2025

A cross-species spatial transcriptomic atlas of the human and non-human primate basal ganglia

The basal ganglia are interconnected subcortical nuclei with complex topographical organization that orchestrate goal-directed behaviors and are implicated in neurodegenerative movement disorders. We generated a cellular-resolution, spatial transcriptomic atlas of the basal ganglia in human, rhesus macaque, and common marmoset, sampling over one million cells in each species. By integrating spatial data with a cross-species, consensus snRNA-seq cell type taxonomy, this atlas reveals conserved principles of molecular organization within and across structures. The cellular architecture is complex but highly stereotyped, with gene expression gradients superimposed onto discrete compartments. Extensive spatial sampling illuminates 3D gradients of molecular organization in the striatum and reveals cell type-specific core and shell compartments in the primate internal globus pallidus, which is conserved with mouse. This unified, cross-species spatial transcriptomic atlas will be a foundational resource for characterizing the molecular and functional organization of the basal ganglia and their roles in health and disease.

neuroscience↗

bioRxiv2025

Spatial patterning of transcriptional and regulatory programs in the primate subcortex

Mammalian brain cell identity is shaped by intrinsic factors and external context. We present a spatially resolved transcriptomic and gene regulatory atlas of cell types across all subcortical regions in a primate, the common marmoset. Dense sampling and cross-species integration revealed spatially precise neuronal assemblies, including in complex midbrain and diencephalic structures. Chromatin accessibility and transcriptional identity are spatially tuned within and across subcortical structures; spatial gradients within hippocampal subfields are orchestrated by graded transcription factors acting through graded enhancers. The primate-expanded thalamic GABAergic population shares transcriptional and regulatory syntax with conserved midbrain populations, reflecting an evolutionary adaptation compared with rodents. Similar regional expression across cell types can arise by distinct regulatory architectures, as for telencephalic astrocytes and neurons. Conversely, distant cell types can share regulatory programs despite divergent identities: striatal GABAergic medium spiny neurons and telencephalic glutamatergic neurons share a postsynaptic regulatory program despite divergent lineage, region, and neurotransmitter identity.

neuroscience↗

bioRxiv2025

Fast Optimization of Robust Transcriptomics Embeddings using Probabilistic Inference Autoencoder Networks for multi-Omics

Advances in single-cell genomics technologies enable the routine acquisition of atlases with millions of cells. These datasets often include multiple covariates, such as donors, sequencing platforms, developmental timepoints, and species, which provide new opportunities for discovery and new challenges. To mitigate unwanted sources of variation, dataset integration is the starting point for most analyses. However, existing methods struggle with integrating large complex datasets. To address these limitations, we developed PIANO, a variational autoencoder framework that uses a negative binomial generalized linear model for stronger batch correction, and code compilation for ten times faster training than existing tools. We first demonstrate performant integration compared to commonly used methods on single-species datasets. We then show PIANO enables superior analyses of multiple atlases, solving challenging integration tasks across sequencing platforms, development, and species, while simultaneously preserving desired biological signals. Our contributions include a novel, high-performance integration method and recommendations for integration applications.

neuroscience↗

bioRxiv2024

A lineage-specific nascent RNA assay unveils principles of gene regulation in tissue biology

Gene regulatory mechanisms that modulate RNA Polymerase II activity are difficult to access in mammalian tissues composed of multiple cell lineages. Here, we develop a nascent RNA assay (PReCIS-seq) that measures lineage-specific transcriptionally-engaged Pol II on genes and DNA enhancer elements in intact mouse tissue. By employing keratinocytes as a prototype lineage, we unearth Pol II promoter-recruitment versus pause-release mechanisms operating in adult skin homeostasis. Moreover, we relate active enhancer proximity and transcription factor binding motifs on promoters to Pol II activity and promoter-proximal pausing level. Finally, we find Pol II firing rapidly into elongation on lineage identity genes and highly paused on cellular safeguarding genes in a context-dependent manner. Our work provides a basic platform to investigate mechanistic principles of gene regulation in individual lineages of complex mammalian tissues.

genomics↗

bioRxiv2024

Conservation, alteration, and redistribution of mammalian striatal interneurons

Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved1-4. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons5. However, there has not yet been a detailed analysis of the spatial and phylogenetic distribution of this population. Here, we profile single cell gene expression in the developing pig (an ungulate) and ferret (a carnivore), representing 94 million years divergence from primates, and assign newborn inhibitory neurons to initial classes first specified during development6. We find that the initial class of TAC3 interneurons represents an ancestral striatal population that is also deployed towards the cortex in pig and ferret. In adult mouse, we uncover a rare population expressing Tac2, the ortholog of TAC3, in ventromedial striatum, prompting a reexamination of developing mouse striatal interneuron initial classes by targeted enrichment of their precursors. We conclude that the TAC3 interneuron initial class is conserved across Boreoeutherian mammals, with the mouse population representing Th striatal interneurons, a subset of which expresses Tac2. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.

evolutionary biology↗

bioRxiv2024

Early-life stress alters postnatal chromatin development in the nucleus accumbens

Early-life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc) -- a key limbic and reward-associated brain region -- ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase Setd7 in juvenile NAc induced lifelong chromatin changes and predominately opened chromatin at long-range cis-regulatory elements predicted to enhance immediate early-genes and transcriptional regulators of mesolimbic development and synaptic activity. These epigenetic changes altered physiological properties of D2-type medium spiny neurons in NAc to resemble neurons of stressed mice, without significantly altering D1-type neurons. Finally, juvenile -- but not adult -- Setd7 overexpression and H3K4me1 enrichment in NAc enhanced behavioral sensitivity to future stress. Together, these data indicate that altered postnatal chromatin development in NAc by H3K4me1 enrichment is sufficient to prime lifelong transcriptional, physiological, and behavioral stress sensitivity.

neuroscience↗