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Success Story - Multiomics (snRNA-Seq / snATAC-Seq) Identifies Dementia Targets

By Stuart P. Atkinson, Ph.D.

December 3, 2024

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Introduction: Delving into Dementia with snRNA-Seq and snATAC-Seq

The pathogenesis of dementia involves specific cell types and brain regions in temporally and spatially distinct patterns (Fu, Hardy, and Duff and Rexach and Geschwind), which makes disease management and treatment particularly challenging. Developing safe and effective therapeutics for dementia, which affects over 28 million people (about the population of Texas) across the globe, requires an understanding of both the shared and disease-specific molecular features in affected human brain cells. While single-cell analyses have begun to define the molecular and cellular underpinnings of Alzheimer’s disease (AD), the cause of 60–70% of dementia cases, few studies have evaluated other forms of dementia.

This significant knowledge gap prompted researchers led by Jessica E. Rexach and Daniel H. Geschwind (University of California, Los Angeles) to generate single-nucleus transcriptomic (snRNA-Seq) and chromatin accessibility (snATAC-Seq) (Buenrostro et al. and Stuart et al.) profiles of the cells resident in brain regions varying in vulnerability and disease burden from post-mortem patients with distinct forms of dementia - AD, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP) - to validate disease-associated cell types and explore the regulatory mechanisms involved. Their exciting findings, published recently in Cell, describe the heterogeneous nature of the cellular, regulatory, and transcriptomic alterations associated with different forms of dementia and apply this information to define potential dementia-wide and disease-specific therapeutic targets (Rexach et al.).

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snRNA-Seq Helps to Define Cell States; snATAC-Seq Describes How

Rexach et al. first employed snRNA-Seq data to identify 9 canonical classes and 24 canonical subclasses of cells resident in the human brain that they employed as a basis to categorize shared and distinct disease-associated cell types. They systematically characterized shared and distinct disease-associated changes across brain regions and forms of dementia to characterize molecular markers and drivers of neuronal vulnerability, neuroinflammation, and resilience.

Analysis of 8 major canonical cell classes (excluding lymphocytes) in 3 brain regions identified 178 cell states representing neuronal and glial cell types/subtypes and their regional localization, distinguishing marker genes, associated biological pathways, transcriptional regulators, and differential gene expression in the three forms of dementia. 49 of the 178 cell states (19 depleted/30 enriched) suffered from a change in composition in one or more forms of dementia, with most observed across multiple forms of dementia; overall, this advanced analysis identified novel shared changes in both neuronal and glial cell states. Analyzing cell types changing for a single form of dementia/brain region to explore differential regional vulnerability across disorders distinguished 3 AD, 8 PSP, and 6 FTD cell types with disease-specific trends. Among these alterations, the snATAC-Seq analysis linked the relaxation of cell-restricted gene expression in PSP astrocytes to the altered regulation of chromatin accessibility (as previously observed in AD) (Xiong et al.).

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snATAC-Seq Helps Define the Factors Driving Neuronal Vulnerability

When seeking to understand those factors driving the relative vulnerability of neuronal subtypes across forms of dementia, the team observed the notable depletion of disorder-specific neuronal subtypes in moderately to highly impacted brain regions, which included intratelencephalic neurons in AD, insular neurons in FTD, and near-projection neurons in PSP in differing brain layers. For PSP, the authors also observed the enrichment of PSP risk genes in near-projection neurons.

A comparison of markers of selectively depleted neurons across forms of dementia revealed examples of shared and distinct genes. The authors noted KCNH7, OPCML, PDE1C, and NLGN1 as shared gene markers in FTD, AD, and PSP and highlighted the elevated level of RORB expression in AD and FTD. Furthermore, they confirmed higher RORB gene promoter occupancy via snATAC-Seq and transcription factor foot printing. Overall, RORB gene targets became downregulated in FTD (alongside reduced chromatin accessibility at RORB binding motifs); additionally, the encoded proteins formed a protein-protein interaction network reflecting coordinated stress responses, whose downregulation suggested a loss of neuroprotective pathway activity.

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Identifying Transcription Factor-Mediated Drivers of Disease-Associated Cell States

This identification of RORB as a potential driver of neuronal vulnerability in multiple forms of dementia suggested the utility of exploring additional transcription factor-mediated drivers of disease-associated cell states. The characterization of cell-type-/disease-type specific gene regulatory networks (validated by snATAC-Seq) in various cell types permitted the identification of specifically active transcription factor sets for each form of dementia and combinations of transcription factor sets that reflected the majority of the gene expression difference associated with disorder-enriched cell types. Distinct clusters of transcription factors co-varied by diagnosis and brain region in microglia, which suggested that distinct transcription factor networks contributed to the diverse microglial transcriptomic states observed across forms of dementia. Finally, the authors interrogated gene regulatory network data for candidate transcription factor regulators that potentially modified resistance to dementia; they identified the regulation of neuroprotective genes by MAFG-NFEL2L1 in excitatory neurons. Interestingly, neurons selectively depleted in one dementia lost MAFG/NFE2L1 regulon activity, consistent with their roles in regulating resilience.

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snRNA-Seq and snATAC-Seq – Paving the Way for the Development of Novel Dementia Therapeutics?

Overall, combined snRNA-Seq and snATAC-Seq analysis supported the description of the pan-dementia and dementia-specific changes in glial/neuronal cell composition, regulatory mechanisms, and gene expression patterns - an undertaking that will hopefully aid the development of novel therapeutic strategies that may help the many, many millions of dementia patients across the globe.

For more details on how snRNA-Seq and snATAC-Seq combine to pave the way toward the development of safe and effective therapeutics for various forms of dementia, see Cell, October 2024.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on Twitter with any questions

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