Genome Architecture Mediates Transcriptional Control of Human Myogenic Reprogramming

Abstract

SummaryGenome architecture has emerged as a critical element of transcriptional regulation, although its role in the control of cell identity is not well understood. Here we use transcription factor (TF)-mediated reprogramming to examine the interplay between genome architecture and transcriptional programs that transition cells into the myogenic identity. We recently developed new methods for evaluating the topological features of genome architecture based on network centrality. Through integrated analysis of these features of genome architecture and transcriptome dynamics during myogenic reprogramming of human fibroblasts we find that significant architectural reorganization precedes activation of a myogenic transcriptional program. This interplay sets the stage for a critical transition observed at several genomic scales reflecting definitive adoption of the myogenic phenotype. Subsequently, TFs within the myogenic transcriptional program participate in entrainment of biological rhythms. These findings reveal a role for topological features of genome architecture in the initiation of transcriptional programs during TF-mediated human cellular reprogramming.

4DNvestigator: Time Series Genomic Data Analysis Toolbox

“…In contrast, betweenness centrality is a more global connectedness measure, which counts the number of times a given node is on the shortest path between all other pairs of nodes. Centrality measures derived from Hi-C have been shown to have biological meaning, reflecting the chromatin accessibility of each region and predicting A/B compartment switch locations [3].…”

“…We define Hi-C matrices of this form as A (m) , where m denotes the time point (or sample). The following network centrality measures are extracted from A (m) : degree, eigenvector, betweenness, and closeness [3]. The centrality measures are combined with the RNA-seq expression for the corresponding genomic regions to form a "feature" matrix that defines the state of each genomic region at each time point.…”

“…A Minimum Area Ellipse (MAE) is calculated if the points lie on a plane. Methods to perform this analysis are described in Algorithm 1, following methods outlined in Liu et al [3].…”

“…We compare this method against established Hi-C comparison methods within this text. We believe adoption by the community at large of analytical tools such as the one described in our [3]. The procedure described by Larntz and Perlman (See section "LP method for comparing Hi-C matrices") detects regions that are most significantly different between samples, and rejects the null hypothesis that these matrices are equal.…”

“…The 4DNvestigator takes a network-based approach to this analysis. This approach allows for the computation of network centrality and network entropy, both of which have been shown to reflect biological phenomena [3,4]. Additionally, we present a novel statistical method for comparing two or more Hi-C matrices.…”