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Peer-reviewedCC BYNeuron

Transcriptional regulation of disease-relevant microglial activation programs

  • Amanda McQuade1,2
  • Reet Mishra3,2
  • Venus Hagan1,2
  • Weiwei Liang1,2
  • Peter J. Colias4,5
  • Vincent Cele Castillo1,2
  • Bianca Gonzalez6,5
  • Justin P. Lubin7,8
  • Verena Claudia Haage9,8
  • Victoria S. Marshe9,8
  • Masashi Fujita9,2
  • Thomas Ta6,2
9 more authors
  • Layla Gomes1,2
  • Olivia M. Teter1,5
  • Xia Han10,8
  • Nathaniel Robichaud11,5
  • Sarah Chasins12,2
  • Jessica E. Rexach13
  • Philip L. De Jager9
  • James K. Nuñez14
  • Martin Kampmann15
15 affiliations
  1. 1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA
  2. 2University of California, San Francisco
  3. 3Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA; UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA
  4. 4Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
  5. 5University of California, Berkeley
  6. 6Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA; Engineering and Technology Department, City College of San Francisco, San Francisco, CA 94112, USA
  7. 7Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA
  8. 8Columbia University Irving Medical Center
  9. 9Center for Translational & Computational Neuroimmunology, Department of Neurology & Taub Institute for the study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10027, USA
  10. 10Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  11. 11Nomic Bio, Montreal, QC, Canada
  12. 12Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
  13. 13Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  14. 14Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
  15. 15Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA; Department for Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected]
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Abstract

Microglia, the brain's innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in induced pluripotent stem cell (iPSC)-derived microglia for inhibitors and activators of six microglial states. We characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models, uncovering protein markers of relevant states. We functionally characterized several multi-state regulators. ZNF532 and PRDM1 knockdown drive disease-associated, lipid-rich signatures and enhance phagocytosis while showing opposing effects on antigen-presentation signatures. DNMT1 knockdown results in widespread loss of DNA methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies.

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Cite

BibTeXRIS
BibTeX
@article{mcquade2026transcriptional,
  title = {{Transcriptional regulation of disease-relevant microglial activation programs}},
  author = {Amanda McQuade and Reet Mishra and Venus Hagan and Weiwei Liang and Peter J. Colias and Vincent Cele Castillo and Bianca Gonzalez and Justin P. Lubin and Verena Claudia Haage and Victoria S. Marshe and Masashi Fujita and Thomas Ta and Layla Gomes and Olivia M. Teter and Xia Han and Nathaniel Robichaud and Sarah Chasins and Jessica E. Rexach and Philip L. De Jager and James K. Nuñez and Martin Kampmann},
  journal = {Neuron},
  year = {2026},
  month = jul,
  doi = {10.1016/j.neuron.2026.07.001},
  url = {https://doi.org/10.1016/j.neuron.2026.07.001},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Transcriptional regulation of disease-relevant microglial activation programs
AU  - Amanda McQuade
AU  - Reet Mishra
AU  - Venus Hagan
AU  - Weiwei Liang
AU  - Peter J. Colias
AU  - Vincent Cele Castillo
AU  - Bianca Gonzalez
AU  - Justin P. Lubin
AU  - Verena Claudia Haage
AU  - Victoria S. Marshe
AU  - Masashi Fujita
AU  - Thomas Ta
AU  - Layla Gomes
AU  - Olivia M. Teter
AU  - Xia Han
AU  - Nathaniel Robichaud
AU  - Sarah Chasins
AU  - Jessica E. Rexach
AU  - Philip L. De Jager
AU  - James K. Nuñez
AU  - Martin Kampmann
PY  - 2026
DA  - 2026/07/01
JO  - Neuron
DO  - 10.1016/j.neuron.2026.07.001
UR  - https://doi.org/10.1016/j.neuron.2026.07.001
AB  - Microglia, the brain's innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in induced pluripotent stem cell (iPSC)-derived microglia for inhibitors and activators of six microglial states. We characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models, uncovering protein markers of relevant states. We functionally characterized several multi-state regulators. ZNF532 and PRDM1 knockdown drive disease-associated, lipid-rich signatures and enhance phagocytosis while showing opposing effects on antigen-presentation signatures. DNMT1 knockdown results in widespread loss of DNA methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies.
SN  - 0896-6273
SN  - 1097-4199
ER  -