Biology subjects

Semick, S. A.

Publications and source records attributed to Semick, S. A..

4 recordsLinked to original sources

bioRxiv2018

Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease

BackgroundLate-onset Alzheimers disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD represented as variation in DNA methylation (DNAm), we surveyed 420,852 DNAm sites from neurotypical controls (N=49) and late-onset AD patients (N=24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum).\n\nResultsWe identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimers disease, such as ANKRD30B.\n\nConclusionsThese results highlight DNAm changes in Alzheimers disease that have gene expression correlates, implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.

genomics↗

bioRxiv2018

Regional heterogeneity in gene expression, regulation and coherence in hippocampus and dorsolateral prefrontal cortex across development and in schizophrenia

Recent large-scale genomics efforts have better characterized the molecular correlates of schizophrenia in postmortem human neocortex, but not hippocampus which is a brain region prominently implicated in its pathogenesis. Here in the second phase of the BrainSeq Consortium (Phase II), we have generated RiboZero RNA-seq data for 900 samples across both the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HIPPO) for 551 individuals (286 affected by schizophrenia disorder: SCZD). We identify substantial regional differences in gene expression, in both pre- and post-natal life, and find widespread differences in how genes are regulated across development. By extending quality surrogate variable analysis (qSVA) to multiple brain regions, we identified 48 and 245 differentially expressed genes (DEG) by SCZD diagnosis (FDR<5%) in HIPPO and DLPFC, respectively, with surprisingly minimal overlap in DEG between the two brain regions. We further identified 205,618 brain region-dependent eQTLs (FDR<1%) and found that 124 GWAS risk loci contain eQTLs in at least one of the regions. We also identify potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia, and suggest future schizophrenia therapeutics may need to target molecular pathologies localized to specific brain regions.

neuroscience↗

bioRxiv2018

Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs

Human induced pluripotent stem cells (hiPSCs) are a powerful model of neural differentiation and maturation. We present a hiPSC transcriptomics resource on corticogenesis from 5 iPSC donor and 13 subclonal lines across nine time points over 5 broad conditions: self-renewal, early neuronal differentiation, neural precursor cells (NPCs), assembled rosettes, and differentiated neuronal cells that were validated using electrophysiology. We identified widespread changes in the expression of individual transcript features and their splice variants, gene networks, and global patterns of transcription. We next demonstrated that co-culturing human NPCs with rodent astrocytes resulted in mutually synergistic maturation, and that cell type-specific expression data can be extracted using only sequencing read alignments without potentially disruptive cell sorting. We lastly developed and validated a computational tool to estimate the relative neuronal maturity of iPSC-derived neuronal cultures and human brain tissue, which were maturationally heterogeneous but contained subsets of cells most akin to adult human neurons.

genomics↗

bioRxiv2017

Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N=33; 16 smoking-exposed) as well as adult (N=207; 57 active smokers) human post-mortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only 2 genes showed significant differential expression (FDR<10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR<10%) - these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in post-mortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer novel insight into the effects of maternal smoking during pregnancy on the prenatal human brain. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.\n\nOne Sentence SummaryMaternal smoking during pregnancy alters the expression of genes within the developing human cortex and these changes are enriched for genes implicated in neuropsychiatric disorders.

neuroscience↗