Biology subjects

Perzel Mandell, K. A.

Publications and source records attributed to Perzel Mandell, K. A..

4 recordsLinked to original sources

bioRxiv2024

Muti-omics characterization reveals brain-wide disruption of synapses and region- and age-specific changes in neurons and glia in Sp4 mutant mice, a genetic model of schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are highly heritable mental illnesses with unclear pathophysiology. Heterozygous loss-of-function mutations of Sp4, a zinc-finger transcription factor, greatly increase risk of schizophrenia and bipolar disorder. To investigate the molecular functions of Sp4 in an unbiased manner in vivo, we performed multi-omics analyses of Sp4 mutant mice. Bulk and single nucleus RNA-seq data showed prominent gene expression changes in all brain regions and most cell types, including neuronal and non-neuronal cells. Gene set enrichment analysis of transcriptomic changes revealed alterations in many molecular pathways, including synapse, oxidative phosphorylation, and ribosome. Synapse proteomics of Sp4 mutants pointed to impaired glutamatergic signaling and altered presynaptic function. In Sp4 heterozygous mutant mice, prefrontal cortex and striatum exhibited downregulation of synapse pathways and neuronal hypoactivity at 1 month, associated with reduced sterol biosynthesis in astrocytes, whereas at 3 months, there was a shift to neuronal hyperactivity, concurrent with suppressed immune pathways in the striatal microglia. Furthermore, our study found that much of the transcriptomic changes might be accounted for by a set of transcription regulators (Nr3c1, Creb1, and Kdm5b) under the control of Sp4. Overall, this study provides cellular and molecular features resulting from Sp4 LoF that may explain the pathophysiology of SCZ-BD psychotic disorder spectrum.

neuroscience↗

bioRxiv2022

Expression Microdissection for use in qPCR based analysis of miRNA in a single cell type

Cell-specific microRNA (miRNA) expression estimates are important in characterizing the localization of miRNA signaling within tissues. Much of this data is obtained from cultured cells, a process known to significantly alter miRNA expression levels. Thus, our knowledge of in vivo cell miRNA expression estimates is poor. We previously demonstrated expression microdissection-miRNA-sequencing (xMD-miRNA-seq) as a means to acquire in vivo estimates, directly from formalin fixed tissues, albeit with limited yield. Here we optimized each step of the xMD process including tissue retrieval, tissue transfer, film preparation, and RNA isolation to increase RNA yields and ultimately show strong enrichment for in vivo miRNA expression by qPCR array. These method improvements, including the development of a non-crosslinked ethylene vinyl acetate (EVA) membrane, resulted in a 23-45 fold increase in miRNA yield, depending on cell type. By qPCR, miR-200a was increased 14-fold in xMD-derived small intestine epithelial cells, with a concurrent 336-fold reduction in miR-143, relative to the matched non-dissected duodenal tissue. xMD is now an optimized method to obtain robust in vivo miRNA expression estimates from cells.

genomics↗

bioRxiv2020

Widespread methylation quantitative trait loci and their role in schizophrenia risk

DNA methylation (DNAm) regulates gene expression and may represent gene-environment interactions. Using whole genome bisulfite sequencing, we surveyed DNAm in a large sample (n=344) of human brain tissues. We identify widespread genetic influence on local methylation levels throughout the genome, with 76% of SNPs and 38% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting putative functional regions that explain much of the heritability associated with risk loci. Furthermore, some CpH sites associated with genetic variation. We have established a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain. One-sentence summaryMost genetic variants associated with DNA methylation levels, and implicated schizophrenia GWAS variants in the human brain.

genomics↗

bioRxiv2019

Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex

DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain is a highly dynamic tissue, but our understanding of key drivers of epigenetic variability across development is limited. We therefore assessed genomic methylation at over 39 million sites in the prenatal cortex using whole genome bisulfite sequencing and found loci and regions in which methylation levels are dynamic across development. We saw that DNAm at these loci was associated with nearby gene expression and enriched for enhancer chromatin states in prenatal brain tissue. Additionally, these loci were enriched for genes associated with psychiatric disorders and genes involved with neurogenesis. We also found autosomal differences in DNAm between the sexes during prenatal development, though these have less clear functional consequences. We lastly confirmed that the dynamic methylation at this critical period is specifically CpG methylation, with very low levels of CpH methylation. Our findings provide detailed insight into prenatal brain development as well as clues to the pathogenesis of psychiatric traits seen later in life.

neuroscience↗