Dataset Information

A map of transcriptional heterogeneity and regulatory variation in human microglia.

ABSTRACT: Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

SUBMITTER: Young AMH

PROVIDER: S-EPMC7610960 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Young Adam M H AMH Kumasaka Natsuhiko N Calvert Fiona F Hammond Timothy R TR Knights Andrew A Panousis Nikolaos N Park Jun Sung JS Schwartzentruber Jeremy J Liu Jimmy J Kundu Kousik K Segel Michael M Murphy Natalia A NA McMurran Christopher E CE Bulstrode Harry H Correia Jason J Budohoski Karol P KP Joannides Alexis A Guilfoyle Mathew R MR Trivedi Rikin R Kirollos Ramez R Morris Robert R Garnett Matthew R MR Timofeev Ivan I Jalloh Ibrahim I Holland Katherine K Mannion Richard R Mair Richard R Watts Colin C Price Stephen J SJ Kirkpatrick Peter J PJ Santarius Thomas T Mountjoy Edward E Ghoussaini Maya M Soranzo Nicole N Bayraktar Omer A OA Stevens Beth B Hutchinson Peter J PJ Franklin Robin J M RJM Gaffney Daniel J DJ

Nature genetics 20210603 6

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants h ...[more]

PMID: 34083789

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Project description:Microglia, the innate immune cells in the central nervous system, exhibit distinct transcriptional profiles across brain regions that are important for facilitating their specialized function. There has been recent interest in identifying the epigenetic modifications associated with these distinct transcriptional profiles, as these may improve our understanding of the underlying mechanisms governing the functional specialization of microglia. One obstacle to achieving this goal is the large number of microglia required to obtain a genome-wide profile for a single histone modification. Given the cellular and regional heterogeneity of the brain, this would require pooling many samples which would impede biological applications that are limited by numbers of available animals. To overcome this obstacle, we have adapted a method of chromatin profiling known as Cleavage Under Targets and Tagmentation (CUT&Tag-Direct) to profile histone modifications associated with regional differences in gene expression throughout the brain reward system. Consistent with previous studies, we find that transcriptional profiles of microglia vary by brain region. However, here we report that these regional differences also exhibit transcriptional network signatures specific to each region. Additionally, we find that these region-dependent network signatures are associated with differential deposition of H3K27ac and H3K7me3, and while the H3K27me3 landscape is remarkably stable across brain regions, the H3K27ac landscape is most consistent with the anatomical location of microglia which explain their distinct transcriptional profiles. Altogether, these findings underscore the established role of H3K27me3 in cell fate determination and support the active role of H3K27ac in the dynamic regulation of microglial gene expression. In this study, we report a molecular and computational framework that can be applied to improve our understanding of the role of epigenetic regulation in microglia in both health and disease, using as few as 2,500 cells per histone mark.

Dataset Information

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Publications

A map of transcriptional heterogeneity and regulatory variation in human microglia.

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