Biology subjects

Schanz, S. J.

Publications and source records attributed to Schanz, S. J..

3 recordsLinked to original sources

bioRxiv2025

Histone hyperacetylation-linked upregulation of KRAB zinc finger proteins impedes glial differentiation in Huntington's disease

Glial differentiation is impaired in Huntington disease (HD), contributing to both the synaptic dysfunction and hypomyelination of HD. Through combined epigenomic and transcriptomic profiling, we found that glial progenitor cells (hGPCs) generated from HD-derived human embryonic stem cells exhibit persistent histone hyperacetylation, enabling the ectopic expression of a broad set of KRAB zinc finger protein (KZFP) transcriptional repressors. Single-cell RNA-Seq analysis of HD hGPCs revealed that their aberrant KZFP expression was attended by the persistent expression of neural progenitor-stage genes relative to wild-type hGPCs. The HD hGPCs over-expressed the MYST family histone acetyltransferase KAT6B, which led to their hyperacetylation at H3K9 and associated DNA demethylation, and displayed abnormally open chromatin, particularly at promoters of chromosome 19 KZFP gene clusters. Among those KZFPs most differentially activated in HD hGPCs was the primate-specific ZNF98, whose overexpression in wild-type hGPCs recapitulated the HD-associated suppression of glial development. These data implicate abnormal histone hyperacetylation in HD glial progenitor cells, and its associated over-expression of recently evolved KZFP transcriptional repressors, as a critical mechanism by which both astrocytic and oligodendrocytic differentiation are impaired in HD.

neuroscience↗

bioRxiv2025

In vivo selection and glymphatic delivery of AAV5 capsids engineered to target human glial progenitor cells

To establish a means of efficiently transducing human glial progenitor cells (hGPCs) in vivo with therapeutic transgenes, we targeted PDGFRA-driven Cre-recombinase expressing hGPCs in human glial chimeric mice with a library of capsid-modified, recombination-reported adeno-associated viruses (AAVs). PCR screening for gliotropic viral capsid sequences, filtered against visceral organs, identified a set of AAV5-based vectors that preferentially infected human GPCs and/or their derived astrocytes and oligodendrocytes in vivo, with minimal systemic infection. To maximize the intracerebral distribution of these viruses while minimizing their dosing and extracerebral spread, we paired their intracisternal delivery with systemic hypertonicity. This method exploited intracerebral glymphatic flow to bypass the blood-brain barrier, delivering AAV directly into the brain parenchyma. Glymphatic delivery of capsid-modified AAV5s, evolved on human GPCs in vivo, thus enables efficient, brain-wide transgene delivery to human glia and their progenitors in the adult brain, with minimal off-target transduction.

neuroscience↗

bioRxiv2025

Charting the transition from in vitro gliogenesis to the in vivo maturation of transplanted human glial progenitor cells

Neither rodent models nor in vitro studies of human cells adequately describe the molecular ontogeny of human glial progenitor cells (hGPCs). Here, we used scRNA-seq together with scATAC-Seq and CUT&TAG assessment of chromatin availability to track the in vitro genesis and in vivo differentiation of hGPCs from pluripotent stem cells (PSCs). In vitro, the hGPC pool comprised 4 transcriptionally-distinct subpopulations, each associated with a distinct pattern of chromatin accessibility and histone modification of stage-dependent genes. After the neonatal transplant of these cells into myelin-deficient shiverer mice, they differentiated further as astrocytes and oligodendrocytes. A combination of gene co-expression, motif enrichment, cell-trajectory, and cell-cell interaction analyses revealed that the host environment potentiated the context-dependent differentiation of the hGPCs, via their activation of distinct gene regulatory networks. Together, these data chart the process by which human PSC-derived GPCs are generated in vitro and diversify in vivo to mature as astrocytes and oligodendrocytes.

neuroscience↗