The landscape of accessible chromatin in quiescent cardiac fibroblasts and cardiac fibroblasts activated after myocardial infarction

Abstract

After myocardial infarction, the massive death of cardiomyocytes leads to cardiac fibroblast proliferation and myofibroblast differentiation, which contributes to the extracellular matrix remodelling of the infarcted myocardium. We recently found that myofibroblasts further differentiate into matrifibrocytes, a newly identified cardiac fibroblast differentiation state. Cardiac fibroblasts of different states have distinct gene expression profiles closely related to their functions. However, the mechanism responsible for the gene expression changes during these activation and differentiation events is still not clear. In this study, the gene expression profiling and genome-wide accessible chromatin mapping of mouse cardiac fibroblasts isolated from the uninjured myocardium and the infarct at multiple time points corresponding to different differentiation states were performed by RNA sequencing (RNA-seq) and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), respectively. ATAC-seq peaks were highly enriched in the promoter area and the distal area where the enhancers are located. A positive correlation was identified between the expression and promoter accessibility for many dynamically expressed genes, even though evidence showed that mechanisms independent of chromatin accessibility may also contribute to the gene expression changes in cardiac fibroblasts after MI. Moreover, motif enrichment analysis and gene regulatory network construction identified transcription factors that possibly contributed to the differential gene expression between cardiac fibroblasts of different states.

Novel Techniques Targeting Fibroblasts after Ischemic Heart Injury

“…This subpopulation exhibits strong proliferativity after MI and studies have shown that fibroblasts present in the infarcted scar originate from several other populations, besides resident cells. Recent studies have identified Tcf21 as a resident fibroblast marker [42].…”

“…For example, early myoFBs may not express αSMA but show a stress fiber network and form focal adhesions termed proto-myofibroblasts [48]. Nonetheless, it is generally accepted that αSMA is a marker for myoFBs [42]. Although myoFB is essential for myocardial healing after ischemia, the persistence of myoFB contributes to maladaptive remodeling and progressive decline of cardiac function.…”

“…Chondrocytes and osteoblasts are cells commonly found in bone, cartilage, and tendon-like tissues suggesting matrifibrocytes to be essential for the maintenance and stabilization of the mature scar. Although these are mainly present after the scar has matured, Comp was recently identified as a marker for this population [42].…”

“…Specifically, in studies involving diagnostics, prevention, and therapy procedures, mice have become an increasingly attractive model due to their short gestational periods, smaller size, larger litter size, low maintenance cost, and more animals being able to be used. Arguably, the most important reason for the use of mouse models in cardiac research is many studies have uncovered that the development of the heart and vasculature is being regulated by similar genes and signaling pathways in both mice and humans [42]. Aside from their ability to be used in surgeries and pharmacological testing, transgenic mice have become a valuable tool in post-MI studies.…”

Fibroblast Memory in Development, Homeostasis and Disease

“…Currently, it is unclear if matrifibrocytes are also present in scar tissue from other organs. By combining ATAC-seq and RNA-seq analysis, a recent study indicates that the martrifibrocyte phenotype is maintained by changes in chromatin accessibility and gene expression [ 46 ] and harnessing this cell plasticity may be therapeutically valuable.…”