Dynamic deployment of H2A.Z positive nucleosome mediated transcriptomic plasticity within vascular smooth muscle cell

To maintain homeostasis in the mature human body, certain differentiated cells adopted high plasticity to refine their cellular functions. However, mechanisms that supported cellular plasticity still remained elusive. Here, through comprehensive transcriptomic and epigenetic studies of highly plastic vascular smooth muscle cells (SMCs), we aimed to decipher the chromatin basis that could mediate cellular plasticity.

In vascular smooth muscle cells, actively transcribed and highly adjustable genes tended to be associated with a continuously accessible region downstream of transcription start site (CAR-downTSS). This CAR-downTSS was located beyond the classic RNA polymerase II paused region, accessible at mono-nucleosome level and incorporated with histone variant H2A.Z. Depletion of H2A.Z reduced active histone modifications within CAR-downTSS, impaired RNA polymerase II transpassing when cells were stimulated, and consequently inhibited the ability of CAR-downTSS-associated genes to adjust their expression. Further in vitro and in vivo studies verified that this CAR-downTSS could be dynamically re-deployed onto different genes in vascular SMCs, whereas it was deployed in smaller quantities and remained quantitatively stable on genome within the quiescent cardiomyocytes.

Vascular SMCs dynamically deployed H2A.Z-positive nucleosomes extending continuously downstream transcription start sites on different genes to support their transcriptional adjustability, which served as an important mechanism mediating cellular plasticity.