Biology subjects

Barragan, C.

Publications and source records attributed to Barragan, C..

9 recordsLinked to original sources

bioRxiv2026

A Multimodal Single-Cell Epigenomic and 3D Genome Atlas of the Human Basal Ganglia

The basal ganglia (BG) underlie motor control, reward processing, and many neurological and psychiatric disorders, but a comprehensive epigenomic and 3D-genome atlas of the human BG is lacking. Here we present a multimodal single-cell atlas profiling DNA methylation and 3D chromatin conformation in 261,331 nuclei (snm3C-seq) across eight subregions, resolving 12 classes, 31 subclasses, and 59 groups. Harmonized under the HMBA basal-ganglia consensus taxonomy, this atlas integrates with matched RNA, ATAC-seq, and histone-modification data across five regulatory layers. We identify millions of cell-type- and region-specific differentially methylated regions enriched for distinct transcription factor motifs and link them to disease-associated heritability. Neuron-specific loops dominate cell-type-specific 3D contact remodeling, while most non-neuron-specific loops are constitutive. Among spiny projection neurons (SPNs), chromatin loops, rather than TAD boundaries, distinguish D1, D2, and eccentric SPN subclasses, with eccentric SPNs showing the most loop-level reorganization among the three. We characterize STR D2 SMYD2-HTR7 SPN, a newly recognized POU6F2 D2-SPN subtype, and reveal region-specific methylation and contact gradients of disease-associated genes, including CADM1 and PDE8B. Integrative gene-regulatory networks reconstruct cell-type-resolved enhancer-promoter links to interpret Parkinsons disease risk variants at SNCA. Finally, MERFISH spatial profiling combined with cross-species Patch-seq identifies non-SPN neuronal subtypes, including a MOXD1 striosomal STR FS PTHLH-PVALB GABA subtype with distinct electrophysiology, partitioning across the striatal matrix-striosome boundary. HighlightsO_LIA multimodal single-cell atlas maps DNA methylation and 3D genome architecture across human basal ganglia cell types and subregions. C_LIO_LINeuron-specific loops dominate cell-type-specific 3D contact remodeling in the human BG, whereas most non-neuron-specific loops are constitutive. C_LIO_LISpiny Projection Neuron (SPN) subtypes exhibit regionally organized epigenomic and 3D genome signatures that align with dorsal-ventral identities. C_LIO_LIChromatin loops are the primary distinguishing feature among D1, D2, and eccentric SPN subclasses, with eccentric SPNs being the most 3D-reorganized. C_LIO_LIIntegrated regulatory maps link cell-type-specific enhancers to disease-associated genetic risk in the human basal ganglia. C_LIO_LINon-SPN interneurons differ in distribution and in transcriptional and epigenetic identity across the matrix-striosome boundary. C_LI

neuroscience↗

bioRxiv2026

Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia

The basal ganglia play essential roles in motor control, emotion, learning and reward processing. Their dysfunction contributes to many neurological and psychiatric disorders. However, the gene regulatory programs defining basal ganglia cell-type identity and function remain poorly understood, limiting interpretation of disease-associated non-coding variants. Here, we present the first single-cell multiome atlas of histone modifications and transcriptomes across eight basal ganglia regions from neurotypical adult human donors. Joint profiling reveals cell-type-specific deployment of active and repressive cis-regulatory elements and gene regulatory networks, and suggests a combinatorial homeobox transcription factor code underlying cell identity. Integration with matched spatial transcriptomic MERFISH data uncovers regional heterogeneity of epigenomic landscapes. Comparative analysis between human and mouse medium spiny neurons uncovers conservation of core gene regulatory features. This atlas interprets non-coding risk variants of neuropsychiatric disorders and supports the development of a deep learning model to predict gene regulation and functional effects of disease-associated variants. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes and three histone modifications across eight human basal ganglia regions characterizes active and repressive chromatin states at cell-type resolution. C_LIO_LICell-type-specific gene regulatory programs decode combinatorial homeobox TF grammar governing the identity and diversification of basal ganglia neurons. C_LIO_LIIntergrative analyses link noncoding neuropsychiatric risk variants to specific cell types, regulatory elements, and candidate target genes. C_LIO_LIA sequence-to-function deep-learning model predicts gene regulation from DNA sequence and prioritizes functional disease-associated variants. C_LI

genomics↗

bioRxiv2026

Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain

Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes with active or repressive histone modification in >750,000 nuclei across adult human brain. C_LIO_LIChromatin state annotation of >500,000 candidate cis-regulatory elements distinguishes active enhancers from accessible and Polycomb-repressed regions. C_LIO_LICell-type-resolved regulatory networks and sequence-based deep learning model prioritize functional neuropsychiatric risk variants. C_LIO_LISpatial epigenomic imputation reveals laminar layer-specific Polycomb repression programs. C_LIO_LIIntegration with 3D genome architecture reveals neuron-specific super long-range chromatin loops silencing early developmental genes. C_LIO_LIEvolutionary analysis uncovers conserved active regulatory grammar but divergent repressive landscape. C_LI

genomics↗

bioRxiv2025

Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease

Alzheimers disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms underlying its region- and cell-type-specific pathogenesis remain poorly defined. Here, we generated a large-scale, single-cell multi-omic atlas--integrating DNA methylation and 3D genome architecture--from postmortem brain tissue of matched AD patients and cognitively normal controls. Samples were collected from three brain regions with distinct vulnerability to AD pathology: the temporal cortex (TC), primary visual cortex (VC), and prefrontal cortex (PFC). Our dataset comprises over 230,000 individual cells, spanning major neuronal and glial populations, and provides a high-resolution view of multi-layer epigenomic regulation. We identified widespread AD-associated DNA methylation changes and marked reorganization of 3D genome structure, including alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops. These changes are strongly region-specific: TC displays pronounced hypermethylation, transcriptional downregulation, and elevated boundary density, whereas VC shows opposing trends and PFC an intermediate profile. We further uncovered previously unrecognized AD-associated glial and neuronal states defined by coordinated epigenomic dysregulation and recurrent genomic deletions, particularly near telomeric regions. This region-resolved, single-cell multi-omic atlas reveals divergent epigenomic trajectories across brain regions and cell types in AD, offering new mechanistic insights and a framework for targeted therapeutic strategies.

genomics↗

bioRxiv2025

DNA Methylation Dynamics of Dose-dependent Acute Exercise, Training Adaptation, and Detraining

Exercise and diet are direct physical contributors to human health, wellness, resilience, and performance1-5. Endurance and resistance training are known to improve healthspan through various biological processes such as mitochondrial function6-8, telomere maintenance9, and inflammaging10. Although several training prescriptions have been defined with specific merits 1,10-20, the long-term effects of these in terms of their molecular alterations have not yet been well explored. In this study, we focus on two combined endurance and resistance training programs: (1) traditional moderate-intensity continuous endurance and resistance exercise (TRAD) and (2) a variation of high-intensity interval training (HIIT) we refer to as high intensity tactical training (HITT), to assess the dynamics of DNA methylation (DNAm) in blood and muscle derived from males (N=23) and females (N=31), over a 12-week period of training followed by a 4-week period of detraining, sampled at pre-exercise and acute time points, totaling 528 samples. Due to its rapid responsiveness to stimuli and its stability, DNAm has been known to facilitate regulatory cascades that significantly affect various physiological processes and pathways. We find that several thousand differentially methylated regions (DMRs) associated with acute exercise in blood, many of which are shared across males and females. This trend is reversed when comparing the baseline (pre-exercise) time points or post-exercise timepoints at the untrained state with those at the post-conditioned state. Here, muscle shows majority of DNAm changes, with most of those being unique. We also find several hundred "memory" DMRs in muscle that maintain the gain or loss of methylation after four weeks of inactivity. Comparing phenotypic measurements, we find specific DMRs that correlate significantly with mitochondrial function and myofiber switching. Using machine learning, we select a subset of DMRs that are most characteristic of training modalities, sex and timepoint. Most of the DMRs are enriched in pathways associated with immune function, cell differentiation, and exercise adaptation. These findings reveal mechanisms by which exercise- and training-induced epigenetic changes alter immune surveillance, mitochondrial function, and inflammatory response, and underscore the relevance of epigenetic plasticity to health monitoring and wellness.

genomics↗

bioRxiv2025

Human Body Single-Cell Atlas of 3D Genome Organization and DNA Methylation

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multi-omic profiling of 3D genome structure and DNA methylation for 86,689 single nuclei across 16 human tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across almost all cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Intriguingly, extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, indicating that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers an extensive reference for exploring gene regulation in human health and disease.

genomics↗

bioRxiv2023

Human Immune Cell Epigenomic Signatures in Response to Infectious Diseases and Chemical Exposures

The epigenomic landscape of human immune cells is dynamically shaped by both genetic factors and environmental exposures. However, the relative contributions of these elements are still not fully understood. In this study, we employed single-nucleus methylation sequencing and ATAC-seq to systematically explore how pathogen and chemical exposures, along with genetic variation, influence the immune cell epigenome. We identified distinct exposure-associated differentially methylated regions (eDMRs) corresponding to each exposure, revealing how environmental factors remodel the methylome, alter immune cell states, and affect transcription factor binding. Furthermore, we observed a significant correlation between changes in DNA methylation and chromatin accessibility, underscoring the coordinated response of the epigenome. We also uncovered genotype-associated DMRs (gDMRs), demonstrating that while eDMRs are enriched in regulatory regions, gDMRs are preferentially located in gene body marks, suggesting that exposures and genetic factors exert differential regulatory control. Notably, disease-associated SNPs were frequently colocalized with meQTLs, providing new cell-type-specific insights into the genetic basis of disease. Our findings underscore the intricate interplay between genetic and environmental factors in sculpting the immune cell epigenome, offering a deeper understanding of how immune cell function is regulated in health and disease.

genomics↗

bioRxiv2019

RPW8/HR Repeats Predict NLR-dependent Hybrid Performance

Hybrid offspring can look very different from their parents, including having greatly increased or decreased fitness. In many plant species, conflicts between divergent elements of the immune system can cause hybrids to express autoimmunity, a generally deleterious syndrome known as hybrid necrosis. We are investigating multiple hybrid necrosis cases in Arabidopsis thaliana that are caused by allele-specific interactions between different variants at two unlinked resistance (R) gene clusters. One is the RESISTANCE TO PERONOSPORA PARASITICA 7 (RPP7) cluster, which encodes an intracellular nucleotide binding site-leucine rich repeat (NLR) immune receptors that confer strain-specific resistance to oomycetes. The other is the RESISTANCE TO POWDERY MILDEW 8 (RPW8)/HOMOLOG OF RPW8 (HR) locus, which encodes atypical resistance proteins that can confer broad-spectrum resistance to filamentous pathogens. There is extensive structural variation in the RPW8/HR cluster, both at the level of gene copy number and at the level of C-terminal protein repeats of unknown function. We demonstrate that the number of RPW8/HR repeats correlate, albeit in a complex manner, with the severity of hybrid necrosis when these alleles are combined with specific RPP7 variants. This observation suggests that gross structural differences, rather than individual amino acid polymorphisms, guide the genetic interaction between RPW8/HR and RPP7 alleles. We discuss these findings in light of the similarity of RPW8/HR proteins with pore-forming toxins, MLKL and HET-S, from mammals and fungi.

genetics↗

bioRxiv2017

A rainfall-manipulation experiment with 517 Arabidopsis thaliana accessions

The gold standard for studying natural selection and adaptation in the wild is to quantify lifetime fitness of individuals from natural populations that have been grown together in a common garden, or that have been reciprocally transplanted. By combining fitness values with species traits and genome sequences, one can infer selection coefficients at the genetic level. Here we present a rainfall-manipulation experiment with 517 whole-genome sequenced natural accessions of the plant Arabidopsis thaliana spanning the global distribution of the species. The experiments were conducted in two field stations in contrasting climates, in the Mediterranean and in Central Europe, where we built rainout shelters and simulated high and low rainfall. Using custom image analysis we quantified fitness- and phenology-related traits for 23,154 pots, which contained about 14,500 plants growing independently, and over 310,000 plants growing in small populations (max. 30 plants). This large field experiment dataset, which associates fitness and ecologically-relevant traits with genomes, will provide an important resource to test eco-evolutionary genetic theories and to understand the potential evolutionary impacts of future climates on an important plant model species.

evolutionary biology↗