Biology subjects

Li, J.-R.

Publications and source records attributed to Li, J.-R..

2 recordsLinked to original sources

bioRxiv2021

Genetic variants associated mRNA stability in lung

Expression quantitative trait loci (eQTLs) analyses have been widely used to identify genetic variants associated with gene expression levels to understand what molecular mechanisms underlie genetic traits. The resultant eQTLs might affect the expression of associated genes through transcriptional or post-transcriptional regulation. In this study, we attempt to distinguish these two types of regulation by identifying genetic variants associated with mRNA stability of genes (stQTLs). Specifically, we computationally inferred mRNA stability of genes based on RNA-seq data and performed association analysis to identify stQTLs. Using the Genotype-Tissue Expression (GTEx) lung RNA-Seq data, we identified a total of 142,801 stQTLs for 3,942 genes and 186,132 eQTLs for 4,751 genes from 15,122,700 genetic variants for 13,476 genes, respectively. Interesting, our results indicated that stQTLs were enriched in the CDS and 3UTR regions, while eQTLs are enriched in the CDS, 3UTR, 5UTR, and upstream regions. We also found that stQTLs are more likely than eQTLs to overlap with RNA binding protein (RBP) and microRNA (miRNA) binding sites. Our analyses demonstrate that simultaneous identification of stQTLs and eQTLs can provide more mechanistic insight on the association between genetic variants and gene expression levels. Author SummaryIn the past decade, many studies have identified genetic variants associated with gene expression level (eQTLs) in different phenotypes, including tissues and diseases. Gene expression is the result of cooperation between transcriptional regulation, such as transcriptional activity, and post-transcriptional regulation, such as mRNA stability. Here, we present a computational framework that take advantage of recently developed methods to estimate mRNA stability from RNA-Seq, which is widely used to estimate gene expression, and then to identify genetic variants associated with mRNA stability (stQTLs) in lung tissue. Compared to eQTLs, we found that genetic variants that affects mRNA stability are more significantly located in the CDS and 3UTR regions, which are known to interact with RNA-binding proteins (RBPs) or microRNAs to regulate stability. In addition, stQTLs are significantly more likely to overlap the binding sites of RBPs. We show that the six RBPs that most significantly bind to stQTLs are all known to regulate mRNA stability. This pipeline of simultaneously identifying eQTLs and stQTLs using only RNA-Seq data can provide higher resolution than traditional eQTLs study to better understand the molecular mechanisms of genetic variants on the regulation of gene expression.

genetics↗

bioRxiv2019

Quantitative modeling links in vivo microstructural and macrofunctional organization of human and macaque insular cortex, and predicts cognitive control abilities

The human insular cortex is a heterogenous brain structure which plays an integrative role in guiding behavior. The cytoarchitectonic organization of the human insula has been investigated over the last century using postmortem brains but there has been little progress in noninvasive in vivo mapping of its microstructure and large-scale functional circuitry. Quantitative modeling of multi-shell diffusion MRI (dMRI) data from 440 HCP participants revealed that human insula microstructure differs significantly across its functionally defined dorsal anterior, ventral anterior, and posterior insula subdivisions that serve distinct cognitive and affective functions. The microstructural organization of the insula was mirrored in its functionally interconnected circuits with the anterior cingulate cortex that anchor the salience network, a system important for adaptive switching of cognitive control systems. Novel validation of the human insula findings came from quantitative dMRI modeling in macaques which revealed microstructural features consistent with known primate insula cytoarchitecture. Theoretical analysis and computer simulations, using realistic 3-dimensional models of neuronal morphology from postmortem tissue, demonstrated that dMRI signals reflect the cellular organization of cortical gray matter, and that these signals are sensitive to cell size and the presence of large neurons such as the von Economo neurons. Crucially, insular microstructural features were linked to behavior and predicted individual differences in cognitive control ability. Our findings open new possibilities for probing psychiatric and neurological disorders impacted by insular cortex dysfunction, including autism, schizophrenia, and fronto-temporal dementia.\n\nStatement of SignificanceThe human insular cortex is a heterogenous brain structure which plays an integrative role in identifying salient sensory, affective, and cognitive cues for guiding attention and behavior. It is also is one of the most widely activated brain regions in all of human neuroimaging research. Here we use novel quantitative tools with in vivo diffusion MRI in large group (N=440) of individuals to uncover several unique microstructural features of the human insula and its macrofunctional circuits. Crucially, microstructural properties of the insular cortex predicted human cognitive control abilities, in agreement with its crucial role in adaptive human behaviors. Our findings open new possibilities for probing psychiatric and neurological disorders impacted by insular dysfunction, including autism, schizophrenia, and fronto-temporal dementia.

neuroscience↗