Biology subjects

Dixon, J.

Publications and source records attributed to Dixon, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Escape from replicative crisis and immortalization precedes complex genome evolution

Shortening of telomeres restricts the proliferative capacity of human somatic cells by inducing replicative senescence and crisis. During cancerous transformation, premalignant cells must overcome these barriers and acquire replicative immortality. Single-cell DNA strand-specific genome sequencing of crisis cells revealed extreme genome instability characterized by complex chromosomal abnormalities. Unexpectedly, spontaneously emerging postcrisis clones showed relatively few and simple structural variants. However, with accumulating divisions following crisis escape, the genomes of immortal postcrisis clones evolve and amass genomic alterations, including tetraploidization events with subsequent losses and gains of individual chromosomes. Our data point towards a new model of tumorigenesis in which crisis acts as a strong selective barrier against cells with aberrant karyotypes, and in which high karyotypic complexity is acquired after immortalization and crisis escape.

cell biology↗

bioRxiv2025

Decoding the Spatial and Epigenetic Logic of Early Skin Development

The embryonic epidermis originates from a simple single-layered ectoderm that undergoes precise transcriptional and morphological transitions to generate a self-replenishing, multi-layered epidermis. A key early milestone is the emergence of the periderm; a transient, protective layer whose disruption underlies a series of devastating human congenital disorders. Despite its importance, the gene regulatory networks that drive periderm formation remain poorly defined. Here, we integrate single-cell multiome profiling with high-resolution spatial transcriptomics analysis in wild-type and transcription factor p63 mutant (Trp63-/-) embryos to dissect the transcriptional and epigenetic programs driving epidermal lineage diversification. We resolve the cellular repertoire of early embryonic skin, define epithelial subpopulations and reconstruct the transcriptional dynamics underlying the periderm emergence. We show that p63 sits at the core of a multilayered enhancer-gene regulatory network, demonstrate how this network is perturbed in vivo, and functionally validate key targets using comparative cellular models. Together, these findings delineate the gene regulatory architecture of early skin development and establish a framework for understanding epithelial-associated congenital disorders.

developmental biology↗

bioRxiv2025

Effects of wasting disease on sea star populations in southern California: Variations over a 40-year period

Sea star wasting disease has been described for asteroid populations from many parts of the world and for numerous species. The causative agents are generally unknown. However, within the Southern California Bight, a Vibrio bacterium appears to have been the cause of wasting disease in the 1980s, and probably the 1990s, during warm water episodes associated with El Ninos. Although a densovirus was implicated in the mass mortality of one species of subtidal sea star during the geographically widespread epizootics that began in 2013, the etiology appears to vary among species, locations, and time periods, and in some cases may not even be associated with a pathogen. We have been studying subtidal benthic communities in southern California since the 1970s and have documented the population effects of wasting disease epizootics associated with warm water El Nino events from 1980 through 2020. Until 2015, population declines coincident with wasting disease were followed by various degrees of recovery, whereas after 2015 there has been little or no recovery at our study sites. Prior to 2013, wasting disease in the northeast Pacific was only reported from locations in the Gulf of California, the southern California bight, and the coast of Vancouver Island, British Columbia. Since 2013, epizootics of wasting disease among sea stars have been observed along the entire west coast of North America. We speculate that the lack of recovery after 2015 may be due to a reduction in larval supply caused by the greater geographical extent of the disease.

ecology↗

bioRxiv2025

Targeted p63 isoform switch corrects dominant mutations in AEC syndrome without disrupting epidermal homeostasis

The transcription factor p63 is a master regulator of stratified epithelial development, and its disruption causes severe congenital defects affecting the skin, limbs, and craniofacial structures in both humans and mice. Among p63-related disorders, Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome is caused by dominant mutations primarily affecting the Sterile Alpha Motif (SAM) domain and the Transactivation Inhibitory Domain (TID) of the TP63 gene, which are unique to the p63 isoform. These mutations promote protein aggregation and transcriptional dysregulation, ultimately leading to debilitating skin erosions, suggesting that isoform-specific strategies could be therapeutically relevant. To explore a therapeutic strategy based on isoform switching, we generated a conditional mouse model with deletion of exon 13, resulting in replacement of p63 by the shorter p63{beta} isoform, which is expressed in the skin at lower levels. Although we found that p63 is required for limb and palate development, p63{beta} proved sufficient to support epidermal formation, postnatal skin homeostasis, and wound healing. At the molecular level, the switch from p63 to p63{beta} preserved chromatin binding and global transcriptional programs in keratinocytes. We next used genome editing to delete exon 13 in human primary keratinocytes, inducing a switch from p63 to p63{beta}. This isoform switch maintained normal proliferation and global gene expression. Importantly, p63{beta} expression in AEC patient-derived keratinocytes rescued protein aggregation, restored mechanical integrity, and normalized epidermal gene expression. Together, these findings demonstrate that p63{beta} can functionally compensate for p63 in the skin and establish and indicate that isoform switching could offer a new treatment option for AEC syndrome.

molecular biology↗

bioRxiv2025

Spatiotemporal Analysis of Remyelination Reveals a Concerted Interferon-Responsive Glial State That Coordinates Immune Infiltration

Remyelination, the process by which axons are re-encased in myelin after injury, is a critical step in restoring brain function, yet the dynamics from initial injury to repair remain poorly characterized. Here, we combined optimized single-nucleus RNA-seq with Slide-seqv2, a high-resolution spatial transcriptomics technology, to densely reconstruct the cellular processes that coordinate remyelination after a focal demyelinating injury. This revealed several findings: First, we found extensive transcriptional diversity of glia and monocyte-derived macrophages from demyelination to repair. Second, we identified a population of infiltrating peripheral lymphocytes--predominantly CD8 T-cells and natural killer cells--that are enriched specifically during remyelination. Third, we identified a concerted interferon-response gene signature that is shared across several cell types--microglia, astrocytes, and the oligodendrocyte lineage--just prior to reestablishment of myelin. These interferon-responsive glia (IRG) form clusters around remyelinating white matter and their formation is solely dependent on the type I interferon receptor. Functionally, we found that IRG secrete the cytokine CXCL10 which mediates infiltration of peripheral lymphocytes into the repairing white matter. Depletion of the most abundant infiltrating lymphocyte, CD8 T-cells, attenuated the differentiation of mature oligodendrocytes during remyelination. Together, our data reveals the diversity of glial-immune interactions that orchestrate white matter repair and a type I-dependent glial state that drives lymphocyte influx into damaged white matter to modulate oligodendrocyte differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/649486v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2c7e07org.highwire.dtl.DTLVardef@1063719org.highwire.dtl.DTLVardef@10b8862org.highwire.dtl.DTLVardef@26dd8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Genome-wide in vivo dynamics of cohesin-mediated loop extrusion and its role in transcription activation

The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here, we utilized acute depletion of NIPBL to characterize the role of cohesin-mediated loop extrusion in vivo. Using this approach, we found that many chromatin loops are rapidly diminished upon loss of NIBPL, consistent with recent single locus imaging studies showing that chromatin loops are transient. However, we also identified cohesin-dependent chromatin loops that are associated with distinct chromatin states and may be "long-lived", given that they require NIPBL for their establishment upon mitotic exit, but are persistent when NIPBL is depleted from interphase cells. In addition to the reformation of 3D genome structures, mitotic exit coincides with widespread transcriptional activation. We found that NIPBL is essential for establishing the expression of lineage-defining genes during the M-G1 transition but has diminished impact on the steady-state maintenance of their expression. At genes sensitive to its depletion, NIPBL supports a unique local genome organization defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.

molecular biology↗

bioRxiv2024

Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.

microbiology↗

bioRxiv2023

Foxp3 Orchestrates Reorganization of Chromatin Architecture to Establish Regulatory T Cell Identity

Chromatin conformation reorganization is emerging as an important layer of regulation for gene expression and lineage specification. Yet, how lineage-specific transcription factors contribute to the establishment of cell type-specific 3D chromatin architecture in the immune cells remains unclear, especially for the late stages of T cell subset differentiation and maturation. Regulatory T cells (Treg) are mainly generated in the thymus as a subpopulation of T cells specializing in suppressing excessive immune responses. Here, by comprehensively mapping 3D chromatin organization during Treg cell differentiation, we show that Treg-specific chromatin structures were progressively established during its lineage specification, and highly associated with Treg signature gene expression. Additionally, the binding sites of Foxp3, a Treg lineage specifying transcription factor, were highly enriched at Treg-specific chromatin loop anchors. Further comparison of the chromatin interactions between wide-type Tregs versus Treg cells from Foxp3 knock-in/knockout or newly-generated Foxp3 domain-swap mutant mouse revealed that Foxp3 was essential for the establishment of Treg-specific 3D chromatin architecture, although it was not dependent on the formation of the Foxp3 domain-swapped dimer. These results highlighted an underappreciated role of Foxp3 in modulating Treg-specific 3D chromatin structure formation.

immunology↗

bioRxiv2022

Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

The human frontal cortex and hippocampus play critical roles in learning and cognition. We investigated the epigenomic and 3D chromatin conformational reorganization during the development of the frontal cortex and hippocampus, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation (sn-m3C-seq). The remodeling of DNA methylation predominantly occurs during late-gestational to early-infant development and is temporally separated from chromatin conformation dynamics. Neurons have a unique Domain-Dominant chromatin conformation that is different from the Compartment-Dominant conformation of glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type differentiation and found putatively causal common variants for schizophrenia strongly overlap with chromatin loop-connected, cell-type-specific regulatory regions. Our data demonstrate that single-cell 3D-regulome is an effective approach for dissecting neuropsychiatric risk loci.

genomics↗

bioRxiv2022

The Nanog epigenetic remodeling complex was essential to vertebrate mesoderm evolution

Pluripotency defines the unlimited potential of cells in the primitive ectoderm of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programing of pluripotency evolved has been obscured by the study of early development in models from lower vertebrates in which pluripotency is not conserved. Here we investigated how the axolotl ortholog of the mammalian core pluripotency factor NANOG, programs pluripotency during axolotl development to model the tetrapod ancestor from which terrestrial vertebrates evolved. We show that in axolotl primitive ectoderm (animal caps; AC) NANOG synergizes with NODAL activity and the epigenetic modifying enzyme DPY30 to direct the deposition of H3K4me3 in chromatin prior to the waves of transcription required for lineage commitment and developmental progression. We show that the interaction of NANOG and NODAL with DPY30 is required to direct development downstream of pluripotency and this is conserved in axolotls and human. These data demonstrate that the interaction of NANOG and NODAL signaling represents the basal state of vertebrate pluripotency.

developmental biology↗

bioRxiv2022

Deciphering the Evolutionary History of Complex Rearrangements in Head and Neck Cancer Patients Using Multi-Omic Approach

Despite the large efforts in international cancer genome consortium studies, there are still a large proportion of tumors with complex genomic rearrangement often remained without a clinically relevant molecular characterization. Integration of multi-omic data helps elucidating evolutionary history of such cases and identifying predictive molecular markers. Here we present the findings of our proof-of-principle study that investigated the evolutionary history of complex rearrangements in primary head and neck tumor genomes integrating long-read whole-genome, Hi-C, and RNA sequencing. We report a HPV-positive case with development of complex genomic rearrangements tracing back to HPV-mediated genomic instability and a HPV-negative case with an enhancer hi-jacking in a region of chromothripsis predicted to co-occur with a neoloop and a super-enhancer. These structural alterations resulted in overexpression of the oncogenes CCND1 and ALK, respectively, validated with immunohistochemistry assay. Furthermore, we introduce a novel analytic approach utilizing long-read whole-genome data distinguishing somatic mutations before and after structural variants. Our findings highlight the need for multi-modal sequencing strategies to increase our understanding of cancer evolution and rare biomarkers in poorly understood cancers.

genomics↗

bioRxiv2022

Oligodendrocyte precursor cells engulf synaptic inputs in an experience- and microglia-dependent manner

Oligodendrocyte precursor cells (OPCs) are a highly proliferative class of non-neuronal progenitors that largely give rise to myelinating oligodendrocytes. Although OPCs persist across the lifespan, their functions beyond oligodendrogenesis remain to be fully characterized. Here, we show that OPCs contribute to neural circuit remodeling by internalizing presynaptic thalamocortical inputs in both the developing and adult mouse visual cortex. Inputs internalized by OPCs localize to lysosomal compartments, consistent with OPC engulfment of synapses occuring through phagocytosis. We further show that engulfment by OPCs is heightened during experience-dependent plasticity, and that this experience-dependent increase in engulfment requires microglia. These data identify a new function for OPCs beyond the generation of oligodendrocytes and reveal that distinct non-neuronal populations collaborate to modulate synaptic connectivity.

neuroscience↗

bioRxiv2021

The landscape of extrachromosomal circular DNA in medulloblastoma

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate "enhancer rewiring" events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.

cancer biology↗

bioRxiv2021

Dynamic regulation and requirement for ribosomal RNA transcription duringmammalian development

Ribosomal RNA (rRNA) transcription by RNA Polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies, which frequently affect craniofacial development. Here, we describe a cellular and molecular mechanism underlying the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCC), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCC particularly sensitive to rRNA synthesis defects. Consistent with this model, NCC-specific deletion of Pol I subunits Polr1a, Polr1c, and associated factor Tcof1 in mice cell-autonomously diminishes rRNA synthesis, which causes an imbalance between rRNA and ribosomal proteins. This leads to increased binding of ribosomal proteins Rpl5 and Rpl11 to Mdm2 and concomitantly diminished binding between Mdm2 and p53. Consequently, p53 protein accumulates, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbates the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins Syndrome and Acrofacial Dysostosis-Cincinnati Type. Altogether, our novel results demonstrate a dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of congenital craniofacial disorders. Significance statementRNA Polymerase I (Pol I) mediated rRNA transcription is required for protein synthesis in all tissues for normal growth and survival as well as for proper embryonic development. Interestingly, disruptions in Pol I mediated transcription perturb ribosome biogenesis and lead to tissue-specific birth defects, which commonly affect the head and face. Our novel results show that during mouse development, Pol I mediated rRNA transcription and protein translation is tissue-specifically elevated in neural crest cells, which give rise to bone, cartilage, and ganglia of the head and face. Using new mouse models, we further show that neural crest cells are highly sensitive to disruptions in Pol I and that when rRNA synthesis is genetically downregulated, it specifically results in craniofacial anomalies.

developmental biology↗

bioRxiv2020

THE CIRCADIAN CLOCK IN THE RETINAL PIGMENT EPITHELIUM CONTROLS THE DIURNAL RHYTHM OF PHAGOCYTIC ACTIVITY

The diurnal peak of phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segments (POS) is under circadian control, and it is believed that this process involves interactions from both the retina and RPE. Previous studies have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. Thereby, the aim of the current study was to determine whether the circadian clock in the retina and or RPE controls the diurnal phagocytic peak of photoreceptor outer segments and whether selective disruption of the circadian clock in the RPE would affect RPE cells function and the viability during aging. To that aim, we first generated and validated an RPE tissue-specific KO of the essential clock gene, Bmal1, and then we determined the daily rhythm in phagocytic activity by the RPE in mice lacking a functional circadian clock in the retina or RPE. Then using electroretinography, spectral domain-optical coherence tomography, and optomotor response measurements of visual function we determined the effect of Bmal1 removal in young (6-month old) and old (18-month old) mice. RPE morphology and lipofuscin accumulation was also determined in young and old mice. Our data show that the circadian clock in the RPE controls the daily diurnal phagocytic peak of POS. Surprisingly, the lack of a functional RPE circadian clock or the diurnal phagocytic peak does not result in any detectable age-related degenerative phenotype in the retina or RPE. Thus, our results demonstrate that the loss of the circadian clock in the RPE or the lack of the daily peak in phagocytosis of POS does not result in deterioration of photoreceptors or the RPE during aging.

neuroscience↗

bioRxiv2020

CTCF Promotes Long-range Enhancer-promoter Interactions and Lineage-specific Gene Expression in Mammalian Cells

Topologically associating domains (TAD) and insulated neighborhoods (INs) have been proposed to constrain enhancer-promoter communications to enable cell-type specific transcription programs, but recent studies show that disruption of TADs and INs resulted in relatively mild changes in gene expression profiles. To better understand the role of chromatin architecture in dynamic enhancer-promoter contacts and lineage-specific gene expression, we have utilized the auxin-inducible degron system to acutely deplete CTCF, a key factor involved in TADs and IN formation, in mouse embryonic stem cells (mESCs) and examined chromatin architecture and gene regulation during neural differentiation. We find that while CTCF depletion leads to global weakening of TAD boundaries and loss of INs, only a minor fraction of enhancer-promoter contacts are lost, affecting a small subset of genes. The CTCF-dependent enhancer-promoter contacts tend to be long-range, spanning hundreds of kilobases, and are established directly by CTCF binding to promoters. Disruption of CTCF binding at the promoter reduces enhancer-promoter contacts and transcription, while artificial tethering of CTCF to the promoter restores the enhancer-promoter contacts and gene activation. Genome-wide analysis of CTCF binding and gene expression across multiple mouse tissues suggests that CTCF-dependent promoter-enhancer contacts may regulate expression of additional mouse genes, particularly those expressed in the brain. Our results uncover both CTCF-dependent and independent enhancer-promoter contacts, and highlight a distinct role for CTCF in promoting enhancer-promoter contacts and gene activation in addition to its insulator function.

genomics↗

bioRxiv2019

Impaired Hippocampal-cortical interactions during sleep and memory reactivation without consolidation in a mouse model of Alzheimer’s disease

Spatial learning is impaired in preclinical Alzheimers disease (AD). We reported similar impairments in 3xTg-AD mice learning a spatial reorientation task. Memory reactivation during sleep is critical for learning related plasticity, and memory consolidation is correlated with hippocampal sharp wave ripple (SWR) density, cortical delta waves (DWs), and their temporal coupling - postulated as a physiological substrate of memory consolidation. Finally, hippocampal-cortical dyscoordination is prevalent in individuals with AD. Thus, we hypothesized impaired memory consolidation mechanisms in hippocampal-cortical networks could account for spatial memory deficits. We assessed sleep architecture, SWR/DW dynamics and memory reactivation in a mouse model of tauopathy and amyloidosis implanted with a recording array targeting isocortex and hippocampus. Mice underwent daily recording sessions of rest-task-rest while learning the spatial reorientation task. We assessed memory reactivation by matching activity patterns from the approach to the unmarked reward zone to patterns during slow wave sleep (SWS). AD mice had more SWS, but reduced SWR density. The increased SWS compensated for reduced SWR density so there was no reduction in SWR number. Conversely, DW density was not reduced so the number of DWs was increased. In control mice hippocampal SWR-cortical DW coupling was strengthened in post-task-sleep and was correlated with performance on the spatial reorientation task the following day. However, in AD mice SWR-DW coupling was reduced and not correlated with behavior, suggesting behavioral decoupling. Thus, reduced SWR-DW coupling may cause impaired learning in AD and may serve as a biomarker for early AD related changes.\n\nSignificance StatementUnderstanding the relationship between network dynamics and cognition early in Alzheimers disease progression is critical for identifying therapeutic targets for earlier treatment. We assessed hippocampal-cortical interactions during sleep in AD mice as a potential cause of early spatial learning and memory deficits. We identified compensatory sleep changes in AD mice, that ameliorated some brain dysfunction. Despite the compensatory changes, impaired spatial navigation and impaired hippocampal-cortical (sharp wave ripple-delta wave) interactions were apparent in AD mice. In control but not AD mice hippocampal-cortical interactions were correlated with performance on the spatial task, the following day, suggesting a potential mechanism of impaired consolidation in AD mice. Thus, changes in hippocampal-cortical brain dynamics during sleep may underlie early memory deficits in AD.

neuroscience↗

bioRxiv2019

Comparing 3D genome organization in multiple species using Phylo-HMRF

Recent developments in whole-genome mapping approaches for the chromatin interactome (such as Hi-C) have offered new insights into 3D genome organization. However, our knowledge of the evolutionary patterns of 3D genome structures in mammalian species remains surprisingly limited. In particular, there are no existing phylogenetic-model based methods to analyze chromatin interactions as continuous features across different species. Here we develop a new probabilistic model, named phylogenetic hidden Markov random field (Phylo-HMRF), to identify evolutionary patterns of 3D genome structures based on multi-species Hi-C data by jointly utilizing spatial constraints among genomic loci and continuous-trait evolutionary models. The effectiveness of Phylo-HMRF is demonstrated in both simulation evaluation and application to real Hi-C data. We used Phylo-HMRF to uncover cross-species 3D genome patterns based on Hi-C data from the same cell type in four primate species (human, chimpanzee, bonobo, and gorilla). The identified evolutionary patterns of 3D genome organization correlate with features of genome structure and function, including long-range interactions, topologically-associating domains (TADs), and replication timing patterns. This work provides a new framework that utilizes general types of spatial constraints to identify evolutionary patterns of continuous genomic features and has the potential to reveal the evolutionary principles of 3D genome organization.

bioinformatics↗