Biology subjects

Davila-Velderrain, J.

Publications and source records attributed to Davila-Velderrain, J..

4 recordsLinked to original sources

bioRxiv2018

Genome-wide active enhancer identification using cell type-specific signatures of epigenomic activity

Recently enhancers have emerged as key players regulating crucial mechanisms such as cell fate determination and establishment of spatiotemporal patterns of gene expression during development. Due to their functional and structural complexity, an accurate in silico identification of active enhancers under specific conditions remain challenging. We present a novel machine learning based method that derives epigenomic patterns exclusively from experimentally characterized active enhancers contrasted with a weighted set of non-enhancer genomic regions. We demonstrate better predictive performance over previous methods, as well as wide generalizability by identifying and annotating active enhancers genome-wide across different tissues/cell types in human and mouse.

bioinformatics↗

bioRxiv2018

DECODE-ing sparsity patterns in single-cell RNA-seq

An inherent challenge in interpreting single-cell transcriptomic data is the high frequency of zero values. This phenomenon has been attributed to both biological and technical sources, although the extent of the contribution of each remains unclear. Here, we show that the underlying gene presence/absence sparsity patterns are by themselves highly informative. We develop an algorithm, called DECODE, to assess the extent of joint presence/absence of genes across different cells, and to infer a gene dependency network. We show that this network captures biologically-meaningful pathways, cell-type specific modules, and connectivity patterns characteristic of complex networks. We develop a model that uses this network to discriminate biological vs. technical zeros, by exploiting each genes local network neighborhood. For inferred non-biological zeros, we build a predictive model that imputes the missing value of each gene based on activity patterns of its most informative neighbors. We show that our framework accurately infers gene-gene functional dependencies, pinpoints technical zeros, and predicts biologically-meaningful missing values in three diverse datasets.

bioinformatics↗

bioRxiv2017

Integrative construction of regulatory region networks in 127 human reference epigenomes by matrix factorization

Despite large experimental and computational efforts aiming to dissect the mechanisms underlying disease risk, mapping cis-regulatory elements to target genes remains a challenge. Here, we introduce a matrix factorization framework to integrate physical and functional interaction data of genomic segments. The framework was used to predict a regulatory network of chromatin interaction edges linking more than 20,000 promoters and 1.8 million enhancers across 127 human reference epigenomes, including edges that are present in any of the input datasets. Our network integrates functional evidence of correlated activity patterns from epigenomic data and physical evidence of chromatin interactions. An important contribution of this work is the representation of heterogeneous data with different qualities as networks. We show that the unbiased integration of independent data sources suggestive of regulatory interactions produces meaningful associations supported by existing functional and physical evidence, correlating with expected independent biological features.

epidemiology↗

bioRxiv2017

Structural robustness of mammalian transcription factor networks reveals plasticity across development

Network biology aims to understand cell behavior through the analysis of underlying complex biomolecular networks. Inference of condition-specific interaction networks from epigenomic data enables the characterization of the structural plasticity that regulatory networks can acquire in different tissues of the same organism. From this perspective, uncovering specific patterns of variation by comparing network structure among tissues could provide insights into systems-level mechanisms underlying cell behavior. Following this idea, here we propose an empirical framework to analyze mammalian tissue-specific networks, focusing on characterizing and contrasting their structure and behavior in response to perturbations. We structurally represent the state of the cell/tissue by condition specific transcription factor networks generated using chromatin accessibility data, and we profile their systems behavior in terms of the structural robustness against random and directed perturbations. Using this framework, we unveil the structural heterogeneity existing among tissues at different levels of differentiation. We uncover a novel and conserved systems property of regulatory networks underlying embryonic stem cells (ESCs): in contrast to terminally differentiated tissues, the promiscuous regulatory connectivity of ESCs produces a globally homogeneous network resulting in increased structural robustness. Possible biological consequences of this property are discussed.

systems biology↗