Single-Cell Dna Methylome and 3D Multi-Omic Atlas of the Adult Mouse Brain

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-seq2 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

Brain-Wide Correspondence of Neuronal Epigenomics and Distant Projections

Single-cell analyses parse the brain’s billions of neurons into thousands of ‘cell-type’ clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use

Northern lights assay: a versatile method for comprehensive detection of DNA damage.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadDNA damage assays have various limitations in types of lesions detected, sensitivity, specificity and samples that can be analyzed. The Northern Lights Assay (NLA) is based on 2D Strandness-Dependent Electrophoresis (2D-SDE), a technique that separates nucleic acids based on length, strandness, structure and conformation changes induced by damage. NLA is run on a microgel platform in 20-25 min. Each specimen is analyzed in pairs of non-digested DNA to detect single- and double-stranded breaks (DSBs) and Mbo I-digested DNA to detect other lesions. We used NLA to evaluate DNA in solution and isolated from human cells treated with various genotoxic agents. NLA detected and distinguished between single- and DSBs, interstrand and intrastrand DNA crosslinks, and denatured single-stranded DNA. NLA was sufficiently sensitive to detect biologically relevant amount of DNA damage. NLA is a versatile, sensitive and simple method for comprehensive and simultaneous analysis of multiple types of damage, both in purified DNA and in DNA isolated from cells and body fluids. NLA can be used to evaluate DNA quality in biosamples, monitor complex molecular procedures, assess genotoxicity, diagnose genome instability, facilitate cancer theranostics and in basic nucleic acids research.University of Iceland Research Fund Landspitali University Hospital Research Fund Icelandic Center for Research Funds Lifeind ehf. University of Iceland Research Fun

Exploring the Term “Resilience” in Arctic Health and Well-Being Using a Sharing Circle as a Community-Centered Approach: Insights from a Conference Workshop

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

Indigenous Engagement in Health Research in Circumpolar Countries : An Analysis of Existing Ethical Guidelines

In this paper, we review existing ethical guidelines that support Circumpolar Indigenous Peoples’ engagement in health research. For this study, we collated national and regional ethical guidelines addressing health research engaging with Indigenous communities. Our study found that ethical guidelines addressing Indigenous engagement in health research have emerged in Canada and the U.S.A. Currently, there are no Indigenous-specific provisions in national guidelines, or legislation concerning health research engaging Indigenous peoples, in Denmark, Finland, Greenland, Norway, Sweden, or Russia. Where guidelines exist, they show considerable variations. We conclude that guidelines are essential to ensure that research undertaken in Indigenous communities is relevant and beneficial to those communities, is conducted respectfully, and that results are appropriately contextualized and accurate. We believe that our analysis might serve as a checklist to support the development of comprehensive guidelines developed by, or at least in partnership with, Arctic Indigenous communities

Indigenous Engagement in Health Research in Circumpolar Countries: An Analysis of Existing Ethical Guidelines

In this paper, we review existing ethical guidelines that support Circumpolar Indigenous Peoples’ engagement in health research. For this study, we collated national and regional ethical guidelines addressing health research engaging with Indigenous communities. Our study found that ethical guidelines addressing Indigenous engagement in health research have emerged in Canada and the U.S.A. Currently, there are no Indigenous-specific provisions in national guidelines, or legislation concerning health research engaging Indigenous peoples, in Denmark, Finland, Greenland, Norway, Sweden, or Russia. Where guidelines exist, they show considerable variations. We conclude that guidelines are essential to ensure that research undertaken in Indigenous communities is relevant and beneficial to those communities, is conducted respectfully, and that results are appropriately contextualized and accurate. We believe that our analysis might serve as a checklist to support the development of comprehensive guidelines developed by, or at least in partnership with, Arctic Indigenous communities

From Resilient to Thriving: Policy Recommendations to Support Health and Well-being in the Arctic

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

Historical foundations and contemporary expressions of a right to health care in Circumpolar Indigenous contexts: A cross-national analysis

Although numerous comparative Indigenous health policy analyses exist in the literature, to date, little attention has been paid to comparative analyses of Circumpolar health policy and the impact these policies may have on Indigenous peoples’ rights to health. In this article, we ground our discussion of Indigenous peoples’ right to access culturally appropriate and responsive health care within the context of the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP). Under UNDRIP, signatory states are obligated to guarantee that Indigenous peoples have access to the same services accessible to all citizens without discrimination. Signatory states must also guarantee access to services that are grounded in Indigenous cultures, medicines, and practices and must address Indigenous peoples’ determinants of health at least to the same extent as their national counterparts. Our analysis finds that the implementation of this declaration varies across the Circumpolar north.The United States recognizes an obligation to provide health care for American Indian and Alaska Native people in exchange for the land that was taken from them. Other countries provide Indigenous citizens access to care in the same health care systems as other citizens. Intercultural models of care exist in Alaska and to some extent across the Canadian territories. However, aside from Sa´ mi Norwegian National Advisory Unit on Mental Health and Substance Use in northern Norway, intercultural models are absent in Nordic countries and in Greenland. While Russia has not ratified UNDRIP, Russian policy guarantees access to health care to all citizens, although access is particularly limited in rural and remote environments, including the Russian Arctic. We conclude that Circumpolar nations should begin and/or expand commitments to culturally appropriate, self-determined, access to health care in Circumpolar contexts to reduce health inequities and adhere to obligations outlined in UNDRIP

Cultural competence and safety in Circumpolar countries: an analysis of discourses in healthcare

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

Diverse methodological approaches to a Circumpolar multi-site case study which upholds and responds to local and Indigenous community research processes in the Arctic

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