Biology subjects

Kong, Y.

Publications and source records attributed to Kong, Y..

5 recordsLinked to original sources

bioRxiv2018

Genetic variants influence on the placenta regulatory landscape

BackgroundFrom genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and whole-genome coverage will have multiple mechanistic and practical implications.\n\nResultsBy producing and analyzing DNA sequence variation (n=303), DNA methylation (n=303) and mRNA expression data (n=80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations.\n\nConclusionsThese findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions.\n\nAuthor summaryThe placenta is a critical organ playing multiple roles including oxygen and metabolite transfer from mother to fetus, hormone production, and vascular perfusion. With this study, we aimed to deliver a placenta-specific regulatory map based on a combination of publicly available and newly generated data. To complete this reference, we obtained genotype information (n=303), DNA methylation (n=303) and expression data (n=80) for placentas from healthy women. Our analysis of methylation and expression quantitative trait loci (QTLs) and correlations between methylation and expression data were designed to identify fundamental associations between genome, transcriptome, and epigenome in this key fetal organ. The results provide high-resolution genetic and epigenetic maps specific to the placenta based on a representative ethnically diverse cohort. As interest and efforts are growing to better understand the etiology of placental disease and the impact of the environment on placental function these data will provide a reference and enhance future investigations.

genomics↗

bioRxiv2018

Transposable Element Expression In Tumors Is Associated With Immune Infiltration And Increased Antigenicity

Profound loss of DNA methylation is a well-recognized hallmark of cancer. Given its role in silencing transposable elements (TEs), we hypothesized that extensive TE expression occurs in tumors with highly demethylated DNA. We developed REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observed increased expression of over 400 TE subfamilies, of which 262 appeared to result from a proximal loss of DNA methylation. The most recurrent TEs were among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent resulted in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing both inflammation and the display of potentially immunogenic neoantigens.\n\nOne Sentence SummaryTransposable element expression in tumors is associated with increased immune response and provides tumor-associated antigens

cancer biology↗

bioRxiv2018

Insights from deconvolution of cell subtype proportions enhance the interpretation of functional genomic data.

Cell subtype proportional differences between samples significantly contribute to variation of functional genomic properties such as gene expression or DNA methylation. Current analytical approaches typically deal with cell subtype proportion influences as a nuisance variable to be eliminated. Here we demonstrate how harvesting information about cell subtype proportions from functional genomics data provides insights into the cellular events in human phenotypes. We note a striking concordance between cell subtype proportions estimated from orthogonal genome-wide assays, and demonstrate the potential for single-cell RNA-seq data to be used in tissues for which reference cell subtype functional genomic datasets are not available. Taken together, our results confirm the importance of estimating cell subtype proportions when testing a model of cellular reprogramming in human phenotypic association studies, and the value of simultaneously testing for systematic cell subtype proportional alterations as a separate phenotypic association, gaining extra insights from functional genomic studies.

genomics↗

bioRxiv2017

Mosaic Chromosomal Aneuploidy Detection By Sequencing (MAD-seq)

Current approaches to detect and characterize mosaic chromosomal aneuploidy are limited by sensitivity, efficiency, cost or the need to culture cells. We describe a combination of a new sequencing-based assay and a novel analytical approach that allows low levels of mosaicism for chromosomal aneuploidy to be detected, assigned to a meiotic or mitotic origin, and quantified as a proportion of the cells in the sample. We show results from a multi-ethnic assay design that is suitable for populations of diverse racial and ethnic origins, and how the MADSEQ analytical approach applied to exome sequencing data reveals unrecognized aneuploidy in 1000 Genomes samples and cell lines from public repositories. We have made the assay design and analytical software open for unrestricted use, with the goal that it can be applied in clinical samples to allow new insights into the unrecognized prevalence of mosaic chromosomal aneuploidy and its phenotypic associations.

genetics↗

bioRxiv2017

Intragenomic Redistribution Of Host Transcription Factor Binding With Toxoplasma gondii Infection

The intracellular pathogen Toxoplasma gondii modifies a number of host cell processes. The mechanisms by which T. gondii alters host gene expression are incompletely understood. This study focuses on how the regulators of gene expression in human host cells respond to T. gondii 24 hours following infection to cause specific patterns of transcriptional dysregulation. The most striking finding was the altered landscape of transposase-accessible chromatin by infection. We found both gains and losses of loci of open chromatin enriched in proximity to transcriptionally altered genes. Both DNA sequence motif analysis at the loci changing chromatin accessibility and network analysis of the genes with transcription and regulatory changes implicate a central role for the AP-1 transcription factor. We validated the redistribution of AP-1 in the host genome using chromatin immunoprecipitation studies of the c-Fos component of AP-1. As infection with T. gondii is associated with the cell failing to progress through the cell cycle, all of the changes observed occur in the absence of cell division and within 24 hours, an insight into the dynamism of these transcriptional regulatory events. We conclude that T. gondii infection influences transcriptional regulation through transcription factor re-targeting to modify the cis-regulatory landscape of the host nucleus.\n\nAUTHOR SUMMARYThe complex interactions between the intracellular pathogen Toxoplasma gondii and the host cell manifest as expression changes of host genes. T. gondiis secreted effectors have been extensively studied and include factors that influence the properties of transcription factors, resulting in post-translational modifications and changes in intracellular localization. To gain insights into how T. gondii exerts specific influences on host transcriptional regulation, we used genome-wide approaches to study gene expression, cytosine modifications, and chromatin structure of the host cell 24 hours after infection. The greatest insights were gained from the mapping of loci of transposase-accessible chromatin, revealing a consistently altered pattern of a subset of loci becoming inaccessible, with the simultaneous acquisition of a new set of infection-associated loci of open chromatin. The sequences at these loci were enriched for certain transcription factor binding motifs, in particular that of AP-1, the transcription factor formed by c-Jun and c-Fos heterodimers. Network analysis revealed a central role for c-Jun and c-Fos in the infection-associated perturbations, prompting a chromatin immunoprecipitation approach that confirmed the redistribution of c-Fos in infected cells. We conclude that a T. gondii infection leads to an intragenomic redistribution of host transcription factor binding, with resulting effects on host gene expression.

genomics↗