scholarly journals Leopard: fast decoding cell type-specific transcription factor binding landscape at single-nucleotide resolution

2019 ◽  
Author(s):  
Hongyang Li ◽  
Yuanfang Guan
Keyword(s):  
Transcription Factor ◽  
Network Architecture ◽  
Characteristic Curve ◽  
Cell Types ◽  
Cell Type ◽  
Single Nucleotide ◽  
Specific Transcription Factor ◽  
Cell Type Specific ◽  
Nucleotide Resolution ◽  
Single Nucleotide Resolution

AbstractDecoding the cell type-specific transcription factor (TF) binding landscape at single-nucleotide resolution is crucial for understanding the regulatory mechanisms underlying many fundamental biological processes and human diseases. However, limits on time and resources restrict the high-resolution experimental measurements of TF binding profiles of all possible TF-cell type combinations. Previous computational approaches either can not distinguish the cell-context-dependent TF binding profiles across diverse cell types, or only provide a relatively low-resolution prediction. Here we present a novel deep learning approach, Leopard, for predicting TF-binding sites at single-nucleotide resolution, achieving the median area under receiver operating characteristic curve (AUROC) of 0.994. Our method substantially outperformed state-of-the-art methods Anchor and FactorNet, improving the performance by 19% and 27% respectively despite evaluated at a lower resolution. Meanwhile, by leveraging a many-to-many neural network architecture, Leopard features hundred-fold to thousand-fold speedup compared to current many-to-one machine learning methods.

scholarly journals A single cell brain atlas in human Alzheimer’s disease

2019 ◽  
Author(s):  
Alexandra Grubman ◽  
Gabriel Chew ◽  
John F. Ouyang ◽  
Guizhi Sun ◽  
Xin Yi Choo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Single Cell ◽  
Cell Fate ◽  
Expression Patterns ◽  
Cell Types ◽  
Gene Expression Patterns ◽  
Cell Type ◽  
Web Resource ◽  
Cell Type Specific

AbstractAlzheimer’s disease (AD) is a heterogeneous disease that is largely dependent on the complex cellular microenvironment in the brain. This complexity impedes our understanding of how individual cell types contribute to disease progression and outcome. To characterize the molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA- seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting specific cellular contributions to global gene expression patterns between control and Alzheimer’s patient brains. We observed distinct cellular regulation of APOE which was repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD subclusters show discordant expression of APOE. Integration of transcription factor regulatory modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under the control of transcription factor EB (TFEB), a master regulator of lysosomal function and which initiated a regulatory cascade containing multiple AD GWAS genes. These results establish functional links between specific cellular sub-populations in AD, and provide new insights into the coordinated control of AD GWAS genes and their cell-type specific contribution to disease susceptibility. Finally, we created an interactive reference web resource which will facilitate brain and AD researchers to explore the molecular architecture of subtype and AD-specific cell identity, molecular and functional diversity at the single cell level.HighlightsWe generated the first human single cell transcriptome in AD patient brainsOur study unveiled 9 clusters of cell-type specific and common gene expression patterns between control and AD brains, including clusters of genes that present properties of different cell types (i.e. astrocytes and oligodendrocytes)Our analyses also uncovered functionally specialized sub-cellular clusters: 5 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological gene categoriesOur analyses found manifold AD GWAS genes specifically associated with one cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated between different brain cell-types in AD sub-cellular clustersWe mapped the regulatory landscape driving transcriptional changes in AD brain, and identified transcription factor networks which we predict to control cell fate transitions between control and AD sub-cellular clustersFinally, we provide an interactive web-resource that allows the user to further visualise and interrogate our dataset.Data resource web interface:http://adsn.ddnetbio.com

Cell type-specific regulation of the Drosophila FMRF-NH2 neuropeptide gene by Apterous, a LIM homeodomain transcription factor

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4757-4765 ◽  
Author(s):  
R.J. Benveniste ◽  
S. Thor ◽  
J.B. Thomas ◽  
P.H. Taghert
Keyword(s):  
Transcription Factor ◽  
Morphological Differentiation ◽  
Cell Types ◽  
Neuroendocrine Cells ◽  
Cell Type ◽  
Homeodomain Transcription Factor ◽  
Neuron Survival ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Lim Homeodomain

We describe the direct and cell-specific regulation of the Drosophila FMRFa neuropeptide gene by Apterous, a LIM homeodomain transcription factor. dFMRFa and Apterous are expressed in partially overlapping subsets of neurons, including two of the seventeen dFMRFa cell types, the Tv neuroendocrine cells and the SP2 interneurons. Apterous contributes to the initiation of dFMRFa expression in Tv neurons, but not in those dFMRFa neurons that do not express Apterous. Apterous is not required for Tv neuron survival or morphological differentiation. Apterous contributes to the maintenance of dFMRFa expression by postembryonic Tv neurons, although the strength of its regulation is diminished. Apterous regulation of dFMRFa expression includes direct mechanisms, although ectopic Apterous does not induce ectopic dFMRFa. These findings show that, for a subset of neurons that share a common neurotransmitter phenotype, the Apterous LIM homeoprotein helps define neurotransmitter expression with very limited effects on other aspects of differentiation.

Sign in / Sign up

Export Citation Format

Share Document