Extensive fragmentation and re-organization of transcription in Systemic Lupus Erythematosus

Abstract

AbstractSystemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. In this work we propose a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). Application of this method on a large transcriptome profiling dataset of 148 SLE patients and 52 healthy individuals enabled the identification of significant disease-associated alterations in gene co-regulation patterns, which also correlate with SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to overall fewer DCEs of smaller size. High disease activity genomes display extensive redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. The dynamics of domain fragmentation and redistribution are associated with SLE clinical endophenotypes, with genes of the interferon pathway being highly enriched in DCEs that become disrupted and with functions associated to more generalized symptoms, being located in domains that emerge anew in high disease activity genomes. Our results suggest strong links between the SLE phenotype and the underlying genome structure and underline an important role for genome organization in shaping gene expression in SLE.