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Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq) 1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation–methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq 2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular–spatial and regulatory genome diversity of the mouse brain. Methylome-based clustering and cross-modality integration with companion datasets from the BRAIN Initiative Cell Census Network enabled the construction of a 3D multi-omic genome atlas of the adult mouse brain featuring thousands of cell-type-specific profiles.

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain's 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq ) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH ) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brain's cellular-spatial and regulatory genome diversity.

Single-cell genetic and epigenetic analyses parse the brain’s billions of neurons into thousands of “cell-type” clusters, each residing in different brain structures. Many of these cell types mediate their unique functions by virtue of targeted long-distance axonal projections to allow interactions between specific cell types. Here we have used Epi-Retro-Seq to link single cell epigenomes and associated cell types to their long-distance projections for 33,034 neurons dissected from 32 different source regions projecting to 24 different targets (225 source →target combinations) across the whole mouse brain. We highlight uses of this large data set for interrogating both overarching principles relating projection cell types to their transcriptomic and epigenomic properties and for addressing and developing specific hypotheses about cell types and connections as they relate to genetics. We provide an overall synthesis of the data set with 926 statistical comparisons of the discriminability of neurons projecting to each target for every dissected source region. We integrate this dataset into the larger, annotated BICCN cell type atlas composed of millions of neurons to link projection cell types to consensus clusters. Integration with spatial transcriptomic data further assigns projection-enriched clusters to much smaller source regions than afforded by the original dissections. We exemplify these capabilities by presenting in-depth analyses of neurons with identified projections from the hypothalamus, thalamus, hindbrain, amygdala, and midbrain to provide new insights into the properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription factor binding motifs, and neurotransmitter usage.

Delineating the gene regulatory programs underlying complex cell types is fundamental for understanding brain functions in health and disease. Here, we comprehensively examine human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in over 500,000 cells from 46 brain regions. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. With these resources, we developed scMCodes that reliably predict brain cell types using their methylation status at select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell type-specific gene regulation in the adult human brain.Competing Interest StatementJ.R.E is a member of the scientific advisor for Zymo Research and Ionis. B.R. is a co-founder and consultant of Arima Genomics Inc. and co-founder of Epigenome Technologies.

This proceedings paper summarizes the first network meeting in the project , held in Copenhagen, Denmark, from 26-28 May 2024. The meeting brought together 31 participants from across the Arctic, including Indigenous and non-Indigenous researchers, students, and health professionals. The aim was to enhance collaboration among circumpolar health networks and to develop a mentorship program supporting young scholars. Sessions included mapping exercises, regional health updates, and discussions on ethics, education, collaboration, and community engagement. Participants identified overlapping mandates, gaps in coordination, and opportunities for joint initiatives across different health networks and societies. The meeting emphasized inclusive, community-based approaches and the integration of Indigenous knowledge. Action items for the coming years include developing and evaluating a model for mentorship in circumpolar health research, enhancing ethical research practices, and continuing the work and conversation of coordinating efforts across health networks. The workshop was concluded with a strong sense of shared purpose and commitment to advancing health and well-being in Arctic communities through strengthened collaborative in both research and education.

Circumpolar Indigenous populations continue to experience dramatic health inequities when compared to their national counterparts. The objectives of this study are first, to explore the space given in the existing literature to the concepts of cultural safety and cultural competence, as it relates to Indigenous peoples in Circumpolar contexts; and second, to document where innovations have emerged. We conducted a review of the English, Danish, Norwegian, Russian and Swedish Circumpolar health literature focusing on Indigenous populations. We include research related to Alaska (USA); the Yukon, the Northwest Territories, Nunavik and Labrador (Canada); Greenland; Sápmi (northmost part of Sweden, Norway, and Finland); and arctic Russia. Our results show that the concepts of cultural safety and cultural competence (cultural humility in Nunavut) are widely discussed in the Canadian literature. In Alaska, the term relationship-centred care has emerged, and is defined broadly to encompass clinician-patient relationships and structural barriers to care. We found no evidence that similar concepts are used to inform service delivery in Greenland, Nordic countries and Russia. While we recognise that healthcare innovations are often localised, and that there is often a lapse before localised innovations find their way into the literature, we conclude that the general lack of attention to culturally safe care for Sámi and Greenlandic Inuit is somewhat surprising given Nordic countries' concern for the welfare of their citizens. We see this as an important gap, and out of step with commitments made under United Nations Declarations on the Rights of Indigenous Peoples. We call for the integration of cultural safety (and its variants) as a lens to inform the development of health programs aiming to improve Indigenous in Circumpolar countries.

In 2018–19, eight Indigenous and non-Indigenous individuals from Canada, Greenland/Denmark, Sweden, and Alaska/United States came together to address research questions relevant to Arctic nations’ shared challenges and opportunities. Our work incorporated critical, community-based perspectives on Arctic health and well-being and promoted strengths-based approaches developed in partnership with Arctic communities. In this article we describe the group’s 16 action-oriented policy recommendations to support health and well-being in the Arctic in four thematic areas: 1) acknowledge and integrate Indigenous rights and knowledges, 2) implement meaningful action to address Indigenous determinants of health, 3) expand health-oriented monitoring and assessment programs, and 4) implement community-led, critical research approaches that focus on partnerships, reciprocity, adherence to ethical guidelines, and funding community-based research. Our recommendations are actionable guidelines for policy and research aimed at reducing inequities, supporting Indigenous expertise and existing knowledge, and promoting thriving communities in the Arctic. En 2018-2019, huit personnes autochtones et non autochtones du Canada, du Groenland (Danemark), de la Suède et de l’Alaska (États-Unis) se sont réunies pour discuter de questions de recherche se rapportant aux défis et aux occasions se présentant dans les nations de l’Arctique. Notre travail a tenu compte de perspectives critiques et communautaires sur la santé et le bien-être dans l’Arctique, en plus de promouvoir des approches fondées sur les points forts, approches élaborées de concert avec des collectivités de l’Arctique. Dans cet article, nous décrivons les 16 recommandations de politiques axées sur des actions formulées par le groupe. Ces recommandations ont pour but de favoriser la santé et le bien-être dans l’Arctique et portent sur quatre grands thèmes : 1) reconnaître et intégrer les droits et les connaissances des Autochtones; 2) mettre en oeuvre des actions significatives tenant compte des déterminants de la santé des Autochtones; 3) élargir les programmes d’évaluation et de surveillance axés sur la santé; et 4) adopter des démarches de recherche critiques dirigées par les collectivités mettant l’accent sur les partenariats, la réciprocité, le respect des lignes directrices en matière d’éthique et le financement de travaux de recherche communautaire. Nos recommandations prennent la forme de lignes directrices réalisables pour donner lieu à des politiques et des recherches visant à réduire les inégalités, à appuyer l’expertise et les connaissances actuelles des Autochtones, et à promouvoir des collectivités florissantes dans l’Arctique.

Beginning January of 2020, COVID-19 cases detected in Arctic countries triggered government policy responses to stop transmission and limit caseloads beneath levels that would overwhelm existing healthcare systems. This review details the various restrictions, health mandates, and transmission mitigation strategies imposed by governments in eight Arctic countries (the United States, Canada, Greenland, Norway, Finland, Sweden, Iceland, and Russia) during the first year of the COVID-19 pandemic, through 31 January 2021s31 January 2021. We highlight formal protocols and informal initiatives adopted by local communities in each country, beyond what was mandated by regional or national governments. This review documents travel restrictions, communications, testing strategies, and use of health technology to track and monitor COVID-19 cases. We provide geographical and sociocultural background and draw on local media and communications to contextualise the impact of COVID-19 emergence and prevention measures in Indigenous communities in the Arctic. Countries saw varied case rates associated with local protocols, governance, and population. Still, almost all regions maintained low COVID-19 case rates until November of 2020. This review was produced as part of an international collaboration to identify community-driven, evidence-based promising practices and recommendations to inform pan-Arctic collaboration and decision making in public health during global emergencies.

This paper outlines the methodological approaches to a multi-site Circumpolar case study exploring the impacts of COVID-19 on Indigenous and remote communities in 7 of 8 Arctic countries. Researchers involved with the project implemented a three-phase multi-site case study to assess the positive and negative societal outcomes associated with the COVID-19 pandemic in Arctic communities from 2020 to 2023. The goal of the multi-site case study was to identify community-driven models and evidence-based promising practices and recommendations that can help inform cohesive and coordinated public health responses and protocols related to future public health emergencies in the Arctic. Research sites included a minimum of 1 one community each from Canada (Nunavut,) United States of America (Alaska), Greenland, Iceland, Norway, Sweden, Finland. The approaches used for our multi-site case study provide a comprehensive, evidence-based account of the complex health challenges facing Arctic communities, offering insights into the effectiveness of interventions, while also privileging Indigenous local knowledge and voices. The mixed method multi-site case study approach enriched the understanding of unique regional health disparities and strengths during the pandemic. These methodological approaches serve as a valuable resource for policymakers, researchers, and healthcare professionals, informing future strategies and interventions.

In the field of Arctic health, “resilience” is a term and concept used to describe capacity to recover from difficulties. While the term is widely used in Arctic policy contexts, there is debate at the community level on whether “resilience” is an appropriate term to describe the human dimensions of health and wellness in the Arctic. Further, research methods used to investigate resilience have largely been limited to Western science research methodologies, which emphasize empirical quantitative studies and may not mirror the perspective of the Arctic communities under study. To explore conceptions of resilience in Arctic communities, a Sharing Circle was facilitated at the International Congress on Circumpolar Health in 2018. With participants engaging from seven of the eight Arctic countries, participants shared critiques of the term “resilience,” and their perspectives on key components of thriving communities. Upon reflection, this use of a Sharing Circle suggests that it may be a useful tool for deeper investigations into health-related issues affecting Arctic Peoples. The Sharing Circle may serve as a meaningful methodology for engaging communities using resonant research strategies to decolonize concepts of resilience and highlight new dimensions for promoting thriving communities in Arctic populations.