Chromatin remodelling appears to be central to determination of SMC phenotypic state, in permitting or denying access of the transcriptional machinery to SMC marker genes, in recruiting transcription factors and co-activators to these genes, and in durably defining the SMC lineage in the face of phenotypic switching. Also crucial is the recruitment or access denial of specific HDACs and HMTs to histones associated with SMC marker CArG regions. Certain histone tail modifications in these areas favour the differentiated SMC phenotype, while their absence occurs with de-differentiation leading to lower expression of SMC markers. These include acetylation of H3K9, H3K14, and H4, and dimethylation of H3K4 and H3K79 (but not methyl-H4K20 and methyl-H3K9, which are markers of several non-SMCs and SMC precursors—see text above). H3K4diMe in particular appears to be a durable marker of the SMC lineage despite changes in differentiation state.
Factors such as KLF4, PRISM, and BRG1/SWI/SNF, act as key suppressors and mediators during this process, interacting with the myocardin family and being altered by phenotype-modifying stimuli while remodelling chromatin. Later studies must define whether and what additional histone modifications exist that alter or determine SMC phenotype, which triggers and co-factors are involved, and whether the observed modifications are the cause or result of SMC differentiation state change.
The HAT p300 has a large and diverse interactome, is present in limiting amounts among competing signalling processes (e.g. differentiation vs. proliferation and growth), modulates both chromatin and transcription factor activity, and itself acts as a myocardin co-activator. In SMCs undergoing differentiation, a decrease in p300 protein levels accompanied by activating covalent modifications may cause the factor to migrate from growth-based pathways to SMC differentiation-specific pathways. Future work must define more precisely the role of p300 in SMC phenotypic determination, along with those of other potentially contributory HATs, such as MYST3, PRMT2, and SRC-1.
Conflicting data surround the exact function of specific HDACs in determining SMC differentiation state, varying in different models. While it appears that relief from HDAC suppression is required for maintaining SMC differentiation, the role of specific HDACs remains to be established. The most consistent data are found for HDAC2 and HDAC5, which both down-regulate SMC marker gene expression. In contrast, HDACs 3, 7, and 8 appear to be key players in the process of SMC differentiation and in regulation of contractile function. The dynamic role of HDACs in SMC plasticity constitutes a rich area of future research.
Many open questions exist. There remains a need for a clear distinction between pericytes, SMCs, and myofibroblasts, as these cells may overlap significantly in structure, function, and contribution to disease processes. Additionally, whether SMCs can truly transdifferentiate to other cell types is unclear. Ultimately, we seek to make use of SMC phenotypic flexibility in the treatment of vascular injury and disease. Further study of SMC chromatin remodelling may provide some answers, and guide us towards new therapeutic options.
Conflict of interest: none declared.