Visual Abstract - A Transcriptomic and Epigenomic Comparison of Fetal and Adult Human Cardiac Fibroblasts Reveals Novel Key Transcription Factors in Adult Cardiac Fibroblasts: 10.1016/j.jacbts.2016.07.007

• The interplay between cardiomyocytes and cardiac fibroblasts is increasingly being recognized as important in cardiac disease.

• Fetal and adult cardiac fibroblasts influence their neighboring cardiomyocytes in different ways. A genome-wide comparison of the 2 reveals that they share >80% of gene transcripts.

• Motif analysis of empirical regulatory elements located next to differentially expressed genes led to identification of key differential regulators of fibroblast identity.

• STAT1 and PLAGL1 were identified and validated as key transcription factors to maintain the adult cardiac fibroblast phenotype. Loss of either factor led to a significant change in phenotype, including smaller cell size, apoptosis, reduced turnover, and down-regulated collagen gene expression.