Biology subjects

Tsai, L.-H.

Publications and source records attributed to Tsai, L.-H..

4 recordsLinked to original sources

bioRxiv2018

Neutools: A collection of bioinformatics web tools for neurogenomic analysis

With a large and growing number of neurogenomic data, from epigenetic, transcriptomic to proteomic data deposited to the public domains, visualization and mining of these data alongside one own data have become extremely useful for identifying potential genetic targets and/or biological pathways to further validate and characterize in model systems. Here, a series of easy-to-use web tools (Neutools) were developed using Shiny/R codes for neuroscientists to perform basic bioinformatics data analysis and visualization. Specifically, NeuVenn calculates and plots overlap statistics for multiple input gene sets; NeuGene and NeuChIP visualize gene expression data and histone ChIP-Seq data generated from brain related tissue and cell culture, respectively. NeuVar annotates human brain GWAS variants and epigenetic features based on user-specified genes and regions. Neutools are freely available resources for all academic users to use.

bioinformatics↗

bioRxiv2018

Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain

Accumulation of tau and amyloid-{beta} are two pathologic hallmarks of Alzheimers disease (AD). Here, we conducted an epigenome-wide association study using the H3K9 acetylation (H3K9Ac) mark in 669 aged human prefrontal cortices: in contrast to amyloid-{beta}, tau protein burden had a broad effect on the epigenome, affecting 5,590 out of 26,384 H3K9Ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segments nuclear lamina association. We confirmed the functional relevance of these chromatin changes by demonstrating (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two AD mouse models. Finally, we found that tau overexpression in iPSC-derived neurons disrupted chromatin organization and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report large-scale tau-driven chromatin rearrangements in the aging human brain that may be reversible with HSP90 inhibitors.

neuroscience↗

bioRxiv2017

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -- one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -- for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL). These data are available for download via the Gene Expression Omnibus (accession GSE101406), and web apps for interacting with this resource are available at https://clue.io/proteomics.\n\nHighlightsO_LIFirst-of-its-kind public resource of proteomic responses to systematically administered perturbagens\nC_LIO_LIDirect proteomic profiling of phosphosignaling and chromatin states in cells for 90 drugs in six different cell lines\nC_LIO_LIExtends Connectivity Map concept to proteomic data for integration with transcriptional data\nC_LIO_LIEnables recognition of unexpected, cell type-specific activities and potential translational therapeutic opportunities\nC_LI

systems biology↗

bioRxiv2017

3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility.

Alzheimers disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (A{beta}) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of A{beta} deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to A{beta} accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early A{beta} aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt A{beta} burden. Finally, we confirm A{beta} in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to A{beta} deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.\n\nAuthor ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.\n\nRGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.\n\nHC built the custom microscope.\n\nRGC, L-HT, KC, ID wrote the manuscript.

neuroscience↗