Biology subjects

Hero, A.

Publications and source records attributed to Hero, A..

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↗

bioRxiv2017

Parental allele-specific genome architecture and transcription during the cell cycle

A normal human somatic cell inherits two haploid genomes. Individual chromosomes of each pair have distinct parental origins and parental alleles are known to unequally contribute to cellular function. We integrated chromosome conformation (form) and gene transcription (function) analyses to dissect the dynamics of the maternal and paternal genomes in lymphoblastoid cells during the cell cycle. We found a distinct set of homologous alleles with very different activity often located close to boundaries of euchromatin and heterochromatin domains. We also identified a set of allele-biased topologically associating domains (TADs) that were small sized and had higher gene density. Thousands of genes show allelically biased expression (ABE) with false discovery rate < 0.05, and 98% of them have no allelic switching during G1, S, and G2/M phases. A subset of ABE genes are preferentially localized near TAD boundaries, enriched with chromatin organization transcription factor binding sites, and contained higher number of sequence variants in CCCTC-binding factor sites. Our results extend previous findings of sequence variation as a basis for unequal functional parental genomes. Investigation of haplotype-resolved form-function dynamics may further our understanding of phenotypic traits, genetic diseases, vulnerability to complex disorders, and the development of cancers.

genomics↗

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↗