Biology subjects

Chen, P.-Y.

Publications and source records attributed to Chen, P.-Y..

3 recordsLinked to original sources

bioRxiv2018

Dynamic Network Analysis of the 4D Nucleome

MotivationFor many biological systems, it is essential to capture simultaneously the function, structure, and dynamics in order to form a comprehensive understanding of underlying phenomena. The dynamical interaction between 3D genome spatial structure and transcriptional activity creates a genomic signature that we refer to as the four-dimensional organization of the nucleus, or 4D Nucleome (4DN). The study of 4DN requires assessment of genome-wide structure and gene expression as well as development of new approaches for data analysis.\n\nResultsWe propose a dynamic multilayer network approach to study the co-evolution of form and function in the 4D Nucleome. We model the dynamic biological system as a temporal network with node dynamics, where the network topology is captured by chromosome conformation (Hi-C), and the function of a node is measured by RNA sequencing (RNA-seq). Network-based approaches such as von Neumann graph entropy, network centrality, and multilayer network theory are applied to reveal universal patterns of the dynamic genome. Our model integrates knowledge of genome structure and gene expression along with temporal evolution and leads to a description of genome behavior on a system wide level. We illustrate the benefits of our model via a real biological dataset on MYOD1-mediated reprogramming of human fibroblasts into the myogenic lineage. We show that our methods enable better predictions on form-function relationships and refine our understanding on how cell dynamics change during cellular reprogramming.\n\nAvailability: The software is available upon request.\n\nContactindikar@umich.edu\n\nSupplementary informationSee Supplementary Material.

bioinformatics↗

bioRxiv2018

A Model for Resource Competition in CRISPR-Mediated Gene Repression

CRISPR-mediated gene regulation is known for its ability to control multiple targets simultaneously due to its modular nature: the same dCas9 effector can target different genes simply by changing the associated gRNA. However, multiplexing requires the sharing of limited amounts of dCas9 proteins among multiple gRNAs, leading to resource competition. In turn, competition between gRNAs for the same resource may hamper network function. In this work, we develop a general model that takes into account the sharing of a limited amount of dCas9 protein for arbitrary CRISPR-mediated gene repression networks. We demonstrate that, as a result of resource competition, hidden interactions appear, that modify the intended network regulations. As a case study, we analyze the effects of these hidden interactions in repression cascades. In particular, we illustrate that perfect adaptation to resource fluctuations can be achieved in cascades with an even number of repressors. In contrast, cascades with an odd number of repressors are substantially impacted by resource competition.

synthetic biology↗

bioRxiv2017

Genome Architecture Leads a Bifurcation in Cell Identity

Genome architecture is important in transcriptional regulation and study of its features is a critical part of fully understanding cell identity. Altering cell identity is possible through overexpression of transcription factors (TFs); for example, fibroblasts can be reprogrammed into muscle cells by introducing MYOD1. How TFs dynamically orchestrate genome architecture and transcription as a cell adopts a new identity during reprogramming is not well understood. Here we show that MYOD1-mediated reprogramming of human fibroblasts into the myogenic lineage undergoes a critical transition, which we refer to as a bifurcation point, where cell identity definitively changes. By integrating knowledge of genome-wide dynamical architecture and transcription, we found significant chromatin reorganization prior to transcriptional changes that marked activation of the myogenic program. We also found that the local architectural and transcriptional dynamics of endogenous MYOD1 and MYOG reflected the global genomic bifurcation event. These TFs additionally participate in entrainment of biological rhythms. Understanding the system-level genome dynamics underlying a cell fate decision is a step toward devising more sophisticated reprogramming strategies that could be used in cell therapies.

cell biology↗