Biology subjects

Chong, F.

Publications and source records attributed to Chong, F..

9 recordsLinked to original sources

bioRxiv2025

Neural stem cell epigenomes and fate bias are temporally coordinated during corticogenesis

The cerebral cortex orchestrates complex cognitive functions, yet how its distinct temporal lineages are molecularly patterned during development remains unresolved. Here, we integrate single-cell transcriptomics and chromatin accessibility, together with genome-wide profiling of DNA methylation and 3D chromosomal contact across mouse corticogenesis (E13-E18) to elucidate cell fate transitions. Using metacell flow analysis, we reveal that neural stem cells (NSCs) progressively shift from a progenitor-biased state toward an astrocytic lineage and that this process is accompanied with changes in DNA methylation and 3D genome organization. A model integrating transcription factor motif affinities with epigenetic features identifies key regulators of cis-regulatory element (CRE) activation. In vivo reporter assays further decouple the intrinsic regulatory potential of CREs from context-dependent synergistic activation. Collectively, our findings uncover temporal epigenomic reprogramming that underlies the evolving differentiation potential of NSCs, providing insights into the intrinsic and extrinsic mechanisms that pattern cortical lineages.

genomics↗

bioRxiv2025

3D Epigenome Evolution Underlies Divergent Gene Regulatory Programs in Primate Neural Development

The expansion of the neocortex is a hallmark of human evolution and is closely linked to neural stem cell biology. Yet, the epigenetic mechanisms driving divergent gene regulation during primate neurogenesis remain elusive. Here, we comprehensively mapped 3D genome organization, chromatin accessibility and gene expression in induced pluripotent stem cells and derived neural stem cells from human, chimpanzee, gorilla and macaque. We identified human-specific epigenetic signatures including cis-regulatory regions and enhancer-promoter interactions and linked them to gene regulatory dynamics. Deep learning models revealed that complex regulatory grammar at cis-regulatory regions, including transcription factor binding sites, local context and higher-order chromatin organization, underlies species and cell type-specific differences. High-resolution Hi-C uncovered unexpected global shifts in 3D genome architecture in chimpanzee and gorilla neural stem cells while topologically associating domains remain remarkably conserved. Notably, species-specific genes interacted with multiple differentially accessible regions, suggesting that synergistic enhancer activation is a key mechanism driving epigenome evolution. These findings provide new insights into the epigenetic basis of primate brain evolution.

genomics↗

bioRxiv2024

Context-dependent epigenome rewiring during neuronal differentiation

Transcription factors (TFs) are pivotal in orchestrating lineage decisions and their binding is often accompanied by chromatin remodeling. However, a comprehensive understanding of how cellular and epigenetic contexts influence TF binding and the subsequent activation of lineage-specific programs remains lacking. Here, we dissected the molecular mechanisms underlying the binding of one such TF - Neurog2 and its functional consequences in two cell-types: mouse embryonic stem cells and neural progenitor cells. Our findings reveal that cell-type-specific chromatin accessibility and motif syntax are key determinants for TF binding. While Neurog2 binding primarily leads to chromatin opening, DNA demethylation and increased chromatin interactions, we also uncovered strong indirect, cell-type-specific effects, which ultimately result in vastly different epigenetic landscape. Furthermore, we identify shared and cell-type-specific Neurog2 interactors, including the SWI/SNF and NuRD complexes. Our study shed light on how cellular environment can modulate TF function to establish lineage identity during development.

genomics↗

bioRxiv2024

Pertpy: an end-to-end framework for perturbation analysis

Advances in single-cell technology have enabled the measurement of cell-resolved molecular states across a variety of cell lines and tissues under a plethora of genetic, chemical, environmental, or disease perturbations. Current methods focus on differential comparison or are specific to a particular task in a multi-condition setting with purely statistical perspectives. The quickly growing number, size, and complexity of such studies requires a scalable analysis framework that takes existing biological context into account. Here, we present pertpy, a Python-based modular framework for the analysis of large-scale perturbation single-cell experiments. Pertpy provides access to harmonized perturbation datasets and metadata databases along with numerous fast and user-friendly implementations of both established and novel methods such as automatic metadata annotation or perturbation distances to efficiently analyze perturbation data. As part of the scverse ecosystem, pertpy interoperates with existing libraries for the analysis of single-cell data and is designed to be easily extended.

bioinformatics↗

bioRxiv2023

Innate immune memory after brain injury drives inflammatory cardiac dysfunction

The enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects of brain injury on systemic immunity have so far been barely investigated. Here, we identified myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Using single-cell sequencing, we identified persistent pro-inflammatory transcriptomic changes in resident monocytes/macrophages in multiple organs one month after experimental ischemic brain injury, which was particularly abundant in the heart and associated with the development of cardiac fibrosis and diastolic dysfunction. A similar phenotype was seen in myocardial autopsy samples from stroke versus control patients. We observed chronic functional changes in myeloid hematopoiesis driven by post-stroke IL-1{beta}-mediated epigenetic changes. These alterations could be transplanted to naive recipient mice and were sufficient to induce cardiac dysfunction. By effectively blocking the trafficking of pro-inflammatory monocytes from the bone marrow to the heart using a dual CCR2/5 inhibitor, we successfully prevented post-stroke cardiac dysfunction. This approach holds promising potential as a novel immune-targeted secondary prevention therapy. We anticipate that the epigenetic immune reprogramming mechanisms detailed here for the brain-heart axis could be generalized to provide a novel framework for explaining the development of various comorbidities after acute tissue injury in remote organs.

immunology↗

bioRxiv2022

High-latitude marginal reefs support fewer but bigger corals than their tropical counterparts

AimDespite the awareness that climate change impacts are typically detrimental to tropical coral reefs, the effect of increasing environmental stress and variability on the population size structure of coral species remains poorly understood. This gap in knowledge limits our ability to effectively conserve coral reef ecosystems because size specific dynamics are rarely incorporated. Our aim is to quantify variation in the size structure of coral populations along a tropical-to-subtropical environmental gradient. Location20 coral populations along a latitudinal gradient on the east coast of Australia ([~]23{degrees}S to 30{degrees}S). Time PeriodBetween 2010 and 2018. Major taxa studiedScleractinian corals. MethodsWe apply two methods to quantify the relationship between environmental covariates and coral population size structure along a latitudinal environmental gradient. First, we use linear regression with summary statistics, such as median size as response variables; a method frequently favoured by ecologists. The second method is compositional functional regression, a novel method using entire size-frequency distributions as response variables. We then predict coral population size structure with increasing environmental stress and variability. ResultsCompared to tropical reefs, we find fewer but larger coral colonies in marginal reefs, where environmental conditions are more variable and stressful for corals in the former. Our model predicts that coral populations may become gradually dominated by larger colonies (> 148 cm2) with increasing environmental stress. Main conclusionsWith increasing environmental stress and variability, we can expect shifts in coral population size structure towards more larger colonies. Fewer but bigger corals suggest low survival, slow growth, and poor recruitment. This finding is concerning for the future of coral reefs as it implies populations may have low recovery potential from disturbances. We highlight the importance and usefulness of continuously monitoring changes to population structure over large spatial scales. Data availabilityData is supplied in the supplementary information, or upon request. Once accepted for publication it will be made openly available on Dryad.

ecology↗

bioRxiv2022

High Concentrations of floating life in the North Pacific Garbage Patch

Floating life (obligate neuston) is a core component of the ocean surface food web. However, only one region of high neustonic abundance is known so far, the Sargasso Sea in the Subtropical North Atlantic, where floating life provides critical habitat structure and ecosystem services. Here, we hypothesize that floating life is also concentrated in other gyres with converging surface currents. To test this hypothesis, we collected samples through the eastern North Pacific Subtropical Gyre in the area of the North Pacific "garbage patch" (NPGP) known to accumulate floating anthropogenic debris. We found that densities of floating life were significantly higher inside the central part of NPGP than on its periphery, and there was a significant positive relationship between neuston abundance and plastic abundance. This work has important implications for the ecology and human impact of subtropical oceanic gyre ecosystems.

ecology↗

bioRxiv2020

Directional phyllotactic bias in calatheas (Goeppertia, Marantaceae): a citizen science approach

Lateral organs arranged in spiral phyllotaxy are separated by the golden angle, {approx}137.5{degrees}, leading to handedness: either clockwise or counter-clockwise. In some species, leaves are asymmetric such that they are smaller and curved towards the side ascending the phyllotactic spiral. As such, these asymmetries lead to mirroring of leaf shapes in plants of opposite phyllotactic handedness. Previous reports had suggested that the pin-stripe calathea (Goeppertia ornata) may be exclusively of one phyllotactic direction, counter-clockwise, but had limited sampling to a single population. Here, we use a citizen science approach leveraging a social media poll, internet image searches, and in-person verification at nurseries in four countries and two continents to demonstrate that calatheas (Goeppertia spp.) around the world are biased towards counter-clockwise phyllotaxy. The possibility that this bias is genetic and its implications for models of phyllotaxy that assume handedness is stochastically specified in equal proportions is discussed.

plant biology↗

bioRxiv2020

Multiomics analysis reveals extensive epigenome remodeling during cortical development

Despite huge advances in stem-cell, single-cell and epigenetic technologies, the precise molecular mechanisms that determine lineage specification remain largely unknown. Applying an integrative multiomics approach, e.g. combining single-cell RNA-seq, single-cell ATAC-seq together with cell-type-specific DNA methylation and 3D genome measurements, we systematically map the regulatory landscape in the mouse neocortex in vivo. Our analysis identifies thousands of novel enhancer-gene pairs associated with dynamic changes in chromatin accessibility and gene expression along the differentiation trajectory. Crucially, we provide evidence that epigenetic remodeling generally precedes transcriptional activation, yet true priming appears limited to a subset of lineage-determining enhancers. Notably, we reveal considerable heterogeneity in both contact strength and dynamics of the generally cell-type-specific enhancer-promoter contacts. Finally, our work suggests a so far unrecognized function of several key transcription factors which act as putative "molecular bridges" and facilitate the dynamic reorganization of the chromatin landscape accompanying lineage specification in the brain.

genomics↗