Discovering the downstream targets of KLF-4 and Estrogen Receptor in primary plaque cells using ChIP-seq.

Abstract

Atherosclerosis is a progressive disease where lipids and fibrous elements accumulate in the walls of the arteries, and this is the primary cause of heart disease and stroke worldwide. Research has shown sex differences in the disease development of atherosclerosis between males and females, with males presenting more unstable lesions while females more often present stable lesions. These sex differences are known and accepted, but the underlying pathobiology of these differences are still largely unknown. The transcription factors KLF-4 and ER were found to play an important role in the disease development of atherosclerosis, so in this study ChIP-seq was performed to unravel the downstream genetic regulation of these transcription factors in plaque primary cells (PCs). This study points to KLF-4 as an important player in the disease progression of atherosclerosis by acting as a repressor. Furthermore, H3K4me2 modification were found associated with target genes involved in the same processes in both PCs and HASMCs and the smooth muscle cell marker genes MYH11 and KLF-4 are active in both cell lines but not in HEK293 cells pointing to a smooth muscle cell origin of PCs. Lastly, fourteen out of the nineteen pre-defined PC specific genes were found to be candidate target genes of either KLF-4 or H3K4me2 in PCs, validating the cultured cell line. These findings can be used in further research to validate the role of KLF-4 in the disease development of atherosclerosis and the role of the found candidate target genes could be further uncovered.