3-deazaneplanocin A

Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8‐cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78‐PERK‐EIF2α‐ATF4‐CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3‐deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high‐fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD‐F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3‐dependent epigenetic regulation. The present study also identifies the H3K27me3‐MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.

Adult T‐cell leukemia (ATL) is an aggressive malignancy caused by human T‐cell leukemia virus type 1 (HTLV‐1) infection. Enhancer of zeste homolog 2 (EZH2) has been implicated in the development and progression of multiple cancers, including virus‐induced malignancies. However, the potential function of EZH2 in HTLV‐1‐induced oncogenesis has not been clearly elucidated. In the present study, we showed that EZH2 was overexpressed and activated in HTLV‐1‐infected cell lines, potentially due to the activation of EZH2 promoter by HTLV‐1 Tax and NF‐κB p65 subunit. In addition, we found that EZH2 enhanced the HBZ‐induced activation of TGF‐β signaling in a histone methyltransferase‐independent manner. As a mechanism for these actions, we found that EZH2 targeted Smad3/Smad4 to form a ternary complex, and the association between Smad3 and Smad4 was markedly enhanced in the presence of EZH2. Knockdown of EZH2 in ATL cells indeed repressed the expressions of the TGF‐β target genes. In particular, EZH2 synergistically enhanced the HBZ/TGF‐β‐induced Foxp3 expression. Treatment of 3‐Deazaneplanocin A, a specific inhibitor of EZH2 significantly inhibited the Foxp3 expression. Taken together, our results suggest that EZH2 may be involved in the differentiation of regulatory T cells through activating the HBZ‐Smad3‐TGF‐β signaling axis, which is considered to be a key strategy for viral persistence.