Biology subjects

Vickers, M. H.

Publications and source records attributed to Vickers, M. H..

6 recordsLinked to original sources

bioRxiv2021

Autism spectrum disorder: understanding the impact of SNPs on biological pathways in the fetal and adult cortex.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and protein-protein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p < 5x10-8) on biological pathways within fetal and adult cortical tissues. We found 80 and 58 SNPs that mark regulatory regions (i.e. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. These eQTLs were also linked to other psychiatric disorders (e.g. schizophrenia, ADHD, bipolar disorder). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Furthermore, we constructed fetal and adult cortex-specific protein-protein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. By contrast in the adult cortex, they largely affect immune pathways. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development.

genomics↗

bioRxiv2019

Decoding the multimorbidities among psychiatric disorders and cognitive functioning

The regulatory contribution that single-nucleotide polymorphisms (SNPs) associated with psychiatric and cognitive phenotypes make to multimorbidity is unknown. Here, we integrate 3D genome organization and expression quantitative trait (eQTL) analyses to identify the genes and biological pathways that are functionally impacted by 2,893 GWAS SNPs associated with cognitive functioning and five psychiatric disorders (i.e. attention deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), unipolar depression (UD) and schizophrenia (SCZ)). The analysis revealed 33 genes and 62 pathways that were commonly affected by the gene regulatory interactions associated with all six phenotypes despite there being no common SNPs and eQTLs. 38 ADHD-, 78 anxiety-, 81 BD-, 169 UD-, 225 SCZ- and 185 cognition-associated genes represent known drug targets. Four genes were affected by eQTLs from all six phenotypes. Collectively, our results represent the foundation for a shift from a gene-targeted towards a pathway-based approach to the treatment of multimorbid conditions.

neuroscience↗

bioRxiv2018

Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines

Cancer cell lines often have large structural variants (SVs) that evolve over time. There are many reported differences in large scale SVs between HL-60 and HL-60/S4, cell lines derived from the same acute promyelocytic leukemia sample. However, the stability and variability of inter- and intra-chromosomal SVs between different sources is unknown. Here, we used Hi-C and RNA-seq to identify and compare large SVs in HL-60 and HL-60/S4 cell lines.\n\nComparisons with previously reported karyotypes identified two non-canonical SVs in HL-60. Ten previously unreported SVs were identified in HL-60/S4. The unreported SVs were generally small enough to be plausibly undetected with traditional karyotyping methods. An expansion centered on MYC was found in a novel genomic location in HL-60. The HL-60 cell line has more within-line structural variation than the HL-60/S4 derivative cell line.\n\nHL-60 and HL-60/S4 karyotypes are generally consistent with the current literature, with some exceptions. Hic_breakfinder is an effective tool for identifying all SVs, but intra-chromosomal SVs are less reliably detected across different samples. The orientation of SV patterns, and strandedness of gene fusions, allowed us to differentiate inversions from other forms of intra-chromosomal SV. Visual inspection of Hi-C heatmap patterns allow further characterization of SVs without additional methods, although orthogonal information such as gene fusions contribute to the characterization.

genomics↗

bioRxiv2018

TNF-α differentially regulates cell cycle genes in promyelocytic and granulocytic HL-60/S4 cells

Tumor necrosis factor alpha (TNF-) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF- are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF- treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes.\n\nTo investigate the interaction between cellular differentiation and TNF-, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF- treatment compared to the undifferentiated promyelocytes. The observed TNF- responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF- treated promyelocytes, and downregulated in TNF- treated granulocytes. This is consistent with TNF- induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, comparisons with gene expression changes associated with differentiation indicated that TNF- treatment of granulocytes shifts the transcriptome towards that of a macrophage.\n\nWe conclude that TNF- treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF- promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF- stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.

genomics↗

bioRxiv2018

Migration through a small pore disrupts inactive chromatin organisation in neutrophil-like cells

BackgroundMammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. Their nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through constricted space, where the nuclear shape must change in order to fit through the constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration.\n\nResultsTotal RNA-sequencing identified that neutrophil migration through 5 or 14m pores was associated with changes in the transcript levels of inflammation and chemotaxis-related genes, when compared to unmigrated cells. Differentially expressed transcripts specific to migration with constriction were enriched for groups of genes associated with cytoskeletal remodeling.\n\nHi-C was used to capture the genome organization in control and migrated cells. Minimal switching was observed between the active (A) and inactive (B) compartments after migration. However, global depletion of short range contacts was observed following migration with constriction compared to migration without constriction. Regions with disrupted contacts, TADs, and compartments were enriched for inactive chromatin.\n\nConclusionShort range genome organization is preferentially altered in inactive chromatin, possibly protecting transcriptionally active contacts from the disruptive effects of migration with constriction. This is consistent with current hypotheses implicating heterochromatin as the mechanoresponsive form of chromatin. Further investigation concerning the contribution of heterochromatin to stiffness, flexibility, and protection of nuclear function will be important for understanding cell migration in human health and disease.

genomics↗

bioRxiv2018

Type 1 diabetes mellitus-associated genetic variants contribute to overlapping immune regulatory networks

Type 1 diabetes (T1D) is a chronic metabolic disorder characterised by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk loci across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue-and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 298 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, CLEC2B, TYK2, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signalling, and programmed cell death protein-1 (PD-1). These pathways have been implicated in the pancreatic beta-cell inflammation and destruction as observed in T1D. Our results demonstrate that T1D-associated variants contribute to adaptive immune signalling, and immune-cell proliferation and activation through tissue and cell-type specific regulatory networks.\n\nAuthor SummaryAlthough genome-wide association studies have identified risk regions across the human genome that predispose individuals to the development of type 1 diabetes (T1D), the mechanisms through which these regions contribute to disease is unclear. Here, we used population-based genetic data from genome-wide association studies (GWAS) to understand how the three-dimensional (3D) organization of the DNA contributes to the differential expression of genes involved in immune system dysregulation as observed in T1D. We identified interconnected regulatory networks that affect immune pathways (adaptive immune signalling and immune-cell proliferation and activation) in a tissue and cell-type specific manner. Some of these pathways are implicated in the pancreatic beta-cell destruction. However, we observed other regulatory changes in tissues that are not typically considered to be central to the pathology of T1D, which represents a novel insight into the disease. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic and therapeutic interventions in T1D.

genetics↗