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<p>The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy. Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility and gene expression across the three conditions, we define cell-type-specific cis-regulatory elements across six cell types and fifty subclasses. Comparing disease-dynamic cis-regulatory elements across three disorders, we find that glia overrepresent disorder-specific gene regulation related to dynamic cellular response to stress. We show that human genetic variants affecting microglial gene regulation converge into distinct and co-regulated modules affecting specific cellular functions. Moreover, polygenic risk modifiers are maximally co-accessible in disorder-specific glial states, modifying distinct pathways such as sphingomyelin regulation in Pick’s disease. Our study informs glial regulators linked to polygenic modifiers of primary tauopathy, establishing modifiable pathways governing resilience.</p>

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Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月14日

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  • Xia Han,
  • Gregory M. Rosenberg,
  • Vivianne M. Kisling,
  • Tao Zhang,
  • Chia-Yi Lee,
  • Ashvin Ravi,
  • Mikhail Melnik,
  • Tina Bilousova,
  • Salvatore Spina,
  • Alissa L. Nana,
  • Lea T. Grinberg,
  • William W. Seeley,
  • Karen H. Gylys,
  • Laura M. Huckins,
  • Towfique Raj,
  • Kristen J. Brennand,
  • Jessica E. Rexach

摘要

The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy. Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility and gene expression across the three conditions, we define cell-type-specific cis-regulatory elements across six cell types and fifty subclasses. Comparing disease-dynamic cis-regulatory elements across three disorders, we find that glia overrepresent disorder-specific gene regulation related to dynamic cellular response to stress. We show that human genetic variants affecting microglial gene regulation converge into distinct and co-regulated modules affecting specific cellular functions. Moreover, polygenic risk modifiers are maximally co-accessible in disorder-specific glial states, modifying distinct pathways such as sphingomyelin regulation in Pick’s disease. Our study informs glial regulators linked to polygenic modifiers of primary tauopathy, establishing modifiable pathways governing resilience.