Biology subjects

Yan, K.-K.

Publications and source records attributed to Yan, K.-K..

4 recordsLinked to original sources

bioRxiv2018

A cross-organism framework for supervised enhancer prediction with epigenetic pattern recognition and targeted validation

Enhancers are important noncoding elements, but they have been traditionally hard to characterize experimentally. Only a few mammalian enhancers have been validated, making it difficult to train statistical models for their identification properly. Instead, postulated patterns of genomic features have been used heuristically for identification. The development of massively parallel assays allows for the characterization of large numbers of enhancers for the first time. Here, we developed a framework that uses Drosophila STARR-seq data to create shape-matching filters based on enhancer-associated meta-profiles of epigenetic features. We combined these features with supervised machine learning algorithms (e.g., support vector machines) to predict enhancers. We demonstrated that our model could be applied to predict enhancers in mammalian species (i.e., mouse and human). We comprehensively validated the predictions using a combination of in vivo and in vitro approaches, involving transgenic assays in mouse and transduction-based reporter assays in human cell lines. Overall, the validations involved 153 enhancers in 6 mouse tissues and 4 human cell lines. The results confirmed that our model can accurately predict enhancers in different species without re-parameterization. Finally, we examined the transcription-factor binding patterns at predicted enhancers and promoters in human cell lines. We demonstrated that these patterns enable the construction of a secondary model effectively discriminating between enhancers and promoters.

bioinformatics↗

bioRxiv2017

Measuring the reproducibility and quality of Hi-C data

Hi-C is currently the most widely used assay to investigate the 3D organization of the genome and to study its role in gene regulation, DNA replication, and disease. However, Hi-C experiments are costly to perform and involve multiple complex experimental steps; thus, accurate methods for measuring the quality and reproducibility of Hi-C data are essential to determine whether the output should be used further in a study. Using real and simulated data, we profile the performance of several recently proposed methods for assessing reproducibility of population Hi-C data, including HiCRep, GenomeDISCO, HiC-Spector and QuASAR-Rep. By explicitly controlling noise and sparsity through simulations, we demonstrate the deficiencies of performing simple correlation analysis on pairs of matrices, and we show that methods developed specifically for Hi-C data produce better measures of reproducibility. We also show how to use established (e.g., ratio of intra to interchromosomal interactions) and novel (e.g., QuASAR-QC) measures to identify low quality experiments. In this work, we assess reproducibility and quality measures by varying sequencing depth, resolution and noise levels in Hi-C data from 13 cell lines, with two biological replicates each, as well as 176 simulated matrices. Through this extensive validation and benchmarking of Hi-C data, we describe best practices for reproducibility and quality assessment of Hi-C experiments. We make all software publicly available at http://github.com/kundajelab/3DChromatin_ReplicateQC to facilitate adoption in the community.

genomics↗

bioRxiv2016

MrTADFinder: A network modularity based approach to identify topologically associating domains in multiple resolutions

Genome-wide proximity ligation based assays such as Hi-C have revealed that eukaryotic genomes are organized into structural units called topologically associating domains (TADs). From a visual examination of the chromosomal contact map, however, it is clear that the organization of the domains is not simple or obvious. Instead, TADs exhibit various length scales and, in many cases, a nested arrangement. Here, by exploiting the resemblance between TADs in a chromosomal contact map and densely connected modules in a network, we formulate TAD identification as an optimization problem and propose an algorithm, MrTADFinder, to identify TADs from intra-chromosomal contact maps. MrTADFinder is based on the network-science concept of modularity. A key component of it is deriving an appropriate background model for contacts in a random chain, by numerically solving a set of matrix equations. The background model preserves the observed coverage of each genomic bin as well as the distance dependence of the contact frequency for any pair of bins exhibited by the empirical map. Also, by introducing a tunable resolution parameter, MrTADFinder provides a self-consistent approach for identifying TADs at different length scales, hence the acronym \"Mr\" standing for Multiple Resolutions. We then apply MrTADFinder to various Hi-C datasets. The identified domains are marked by boundary signatures in chromatin marks and transcription factor (TF) that are consistent with earlier work. Moreover, by calling TADs at different length scales, we observe that boundary signatures change with resolution, with different chromatin features having different characteristic length scales. Furthermore, we report an enrichment of HOT regions near TAD boundaries and investigate the role of different TFs in determining boundaries at various resolutions. To further explore the interplay between TADs and epigenetic marks, we examine how somatic mutations are distributed across boundaries (as tumor mutational burden is known to be coupled to chromatin structure), finding a clear stepwise pattern. Overall, MrTADFinder provides a novel computational framework to explore the multi-scale structures in Hi-C contact maps.\n\nAuthor SummaryThe accommodation of the roughly 2m of DNA in the nuclei of mammalian cells results in an intricate structure, in which the topologically associating domains (TADs) formed by densely interacting genomic regions emerge as a fundamental structural unit. Identification of TADs is essential for understanding the role of 3D genome organization in gene regulation. By viewing the chromosomal contact map as a network, TADs correspond to the densely connected regions in the network. Motivated by this mapping, we propose a novel method, MrTADFinder, to identify TADs based on the concept of modularity in network science. Using MrTADFinder, we identify domains at various resolutions, and further explore the interplay between domains and other chromatin features like transcription factors binding and histone modifications at different resolutions. Overall, MrTADFinder provides a new computational framework to investigate the multiple length scales that are built inside the organization of the genome.

genomics↗

bioRxiv2016

HiC-Spector: A matrix library for spectral and reproducibility analysis of Hi-C contact maps

SummaryGenome-wide proximity ligation based assays like Hi-C have opened a window to the 3D organization of the genome. In so doing, they present data structures that are different from conventional 1D signal tracks. To exploit the 2D nature of Hi-C contact maps, matrix techniques like spectral analysis are particularly useful. Here, we present HiC-spector, a collection of matrix-related functions for analyzing Hi-C contact maps. In particular, we introduce a novel reproducibility metric for quantifying the similarity between contact maps based on spectral decomposition. The metric successfully separates contact maps mapped from Hi-C data coming from biological replicates, pseudo-replicates and different cell types.\n\nAvailabilitySource code in Julia and the documentation of HiC-spector can be freely obtained at https://github.com/gersteinlab/HiC_spector\n\nContactpi@gersteinlab.org

bioinformatics↗