Biology subjects

Mansky, B.

Publications and source records attributed to Mansky, B..

4 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

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↗

bioRxiv2021

Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

BackgroundA strong predictor for the development of alcohol use disorders (AUDs) is altered sensitivity to the intoxicating effects of alcohol. Individual differences in the initial sensitivity to alcohol are controlled in part by genetic factors. Mice offer a powerful tool for elucidating the genetic basis of behavioral and physiological traits relevant to AUDs; but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations allow for the opportunity to observe a wider range of phenotypic variation, offer greater mapping precision, and thus increase the potential for efficient gene identification. MethodsWe have taken advantage of the Diversity Outbred (DO) mouse population to identify and precisely map quantitative trait loci (QTL) associated with ethanol sensitivity. We phenotyped 798 male J:DO mice for three measures of ethanol sensitivity: ataxia, hypothermia, and loss of the righting response. We used high density MEGAMuga and GIGAMuga arrays to obtain genotypes ranging from 77,808 - 143,259 SNPs. In addition, we performed RNA sequencing in striatum to map expression QTLs and to identify gene expression-trait correlations. ResultsWe then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exist between DNA sequence, gene expression values and ethanol-related phenotypes to prioritize our list of positional candidate genes. ConclusionsOur results can be used to identify alleles that contribute to AUDs in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

genetics↗

bioRxiv2021

Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal and ventral adult neurogenic lineages

The ventricular-subventricular zone (V-SVZ) is home to the largest neurogenic niche in the adult mouse brain. Previous work has demonstrated that resident stem cells in different locations within the V-SVZ produce different subtypes of new neurons for the olfactory bulb. While great progress has been made in understanding the differences in regional stem cell potential using viral and genetic lineage tracing strategies, the core molecular heterogeneity that underlies these regional differences is largely unknown. Here we present single whole-cell and single nucleus sequencing datasets of microdissected adult mouse V-SVZ, and evidence for the existence of two broad populations of adult neural stem cells. By using spatially resolved microdissections in the single nucleus sequencing dataset as a reference, and mapping marker gene expression in the V-SVZ, we find that these two populations reside in largely non-overlapping domains in either the dorsal or ventral V-SVZ. Furthermore, we identified two subpopulations of newly born neurons that have gene expression consistent with dorsal or ventral origins. Finally, we identify genes expressed by both stem cells and the neurons they generate that specifically mark either the dorsal or ventral adult neurogenic lineage. These datasets, methods and findings will facilitate the study of region-specific regulation of adult neurogenesis.

neuroscience↗