Gene expression in mammalian cells depends on the epigenetic status of the chromatin, including DNA methylation, histone modifications, promoter–enhancer interactions, and noncoding RNA–mediated regulation. The coordinated actions of these multifaceted regulations determine cell development, cell cycle regulation, cell state and fate, and the ultimate responses in health and disease. Therefore, studies of epigenetic modulations are critical for our understanding of gene regulation mechanisms at the molecular, cellular, tissue, and organ levels. The aim of this review is to provide biomedical engineers with an overview of the principles of epigenetics, methods of study, recent findings in epigenetic regulation in health and disease, and computational and sequencing tools for epigenetics analysis, with an emphasis on the cardiovascular system. This review concludes with the perspectives of the application of bioengineering to advance epigenetics and the utilization of epigenetics to translate bioengineering research into clinical medicine.

Invasive micropapillary carcinoma (IMPC) has very high rates of lymphovascular invasion and lymph node metastasis and has been reported in several organs. However, the genomic mechanisms underlying its metastasis are unclear. Here, we perform whole-genome sequencing of tumor cell clusters from primary IMPC and paired axillary lymph node metastases. Cell clusters in multiple lymph node foci arise from a single subclone of the primary tumor. We find evidence that the monoclonal metastatic ancestor in primary IMPC shares high frequency copy-number loss of PRDM16 and IGSF9 and the copy number gain of ALDH2. Immunohistochemistry analysis further shows that low expression of IGSF9 and PRDM16 and high expression of ALDH2 are associated with lymph node metastasis and poor survival of patients with IMPC. We expect these genomic and evolutionary profiles to contribute to the accurate diagnosis of IMPC.

Invasive micropapillary carcinoma (IMPC) is a special histological subtype of breast cancer, featured with extremely high rates of lymphovascular invasion and lymph node metastasis. Based on a previous series of studies, our team proposed the hypothesis of “clustered metastasis of IMPC tumor cells”. However, the transcriptomics characteristics underlying its metastasis are unknown, especially in spatial transcriptomics (ST). In this paper, we perform ST sequencing on four freshly frozen IMPC samples. We draw the transcriptomic maps of IMPC for the first time and reveal its extensive heterogeneity, associated with metabolic reprogramming. We also find that IMPC subpopulations with abnormal metabolism are arranged in different spatial areas, and higher levels of lipid metabolism are observed in all IMPC hierarchical clusters. Moreover, we find that the stromal regions show varieties of gene expression programs, and this difference depends on their distance from IMPC regions. Furthermore, a total of seven IMPC hierarchical clusters of four samples share a common higher expression level of the SREBF1 gene. Immunohistochemistry results further show that high SREBF1 protein expression is associated with lymph node metastasis and poor survival in IMPC patients. Together, these findings provide a valuable resource for exploring the inter- and intra-tumoral heterogeneity of IMPC and identify a new marker, SREBF1, which may facilitate accurate diagnosis and treatment of this disease.

Invasive micropapillary carcinoma (IMPC) is a special histopathological subtype of breast cancer. Clinically, IMPC exhibits a higher incidence of lymphovascular invasion and lymph node metastasis compared with that of invasive ductal carcinoma (IDC), the most common type. However, the metabolic characteristics and related mechanisms underlying malignant IMPC biological behaviors are unknown. We performed large‐scale targeted metabolomics analysis on resected tumors obtained from chemotherapy‐naïve IMPC (n = 25) and IDC (n = 26) patients to investigate metabolic alterations, and we integrated mass spectrometry analysis, RNA sequencing, and ChIP‐sequencing data to elucidate the potential molecular mechanisms. The metabolomics revealed distinct metabolic profiles between IMPC and IDC. For IMPC patients, the metabolomic profile was characterized by significantly high levels of arginine methylation marks, and protein arginine methyltransferase 3 (PRMT3) was identified as a critical regulator that catalyzed the formation of these arginine methylation marks. Notably, overexpression of PRMT3 was an independent risk factor for poor IMPC prognosis. Furthermore, we demonstrated that PRMT3 was a key regulator of breast cancer cell proliferation and metastasis both in vitro and in vivo, and treatment with a preclinical PRMT3 inhibitor decreased the xenograft tumorigenic capacity. Mechanistically, PRMT3 regulated the endoplasmic reticulum (ER) stress signaling pathway by facilitating histone H4 arginine 3 asymmetric dimethylation (H4R3me2a), which may endow breast cancer cells with great proliferative and metastatic capacity. Our findings highlight PRMT3 importance in regulating the malignant biological behavior of IMPC and suggest that small‐molecule inhibitors of PRMT3 activity might be promising breast cancer treatments.