Neural tube defects (NTDs) are serious congenital malformations. Excessive maternal homocysteine (Hcy) increases the risk of NTDs, while its mechanism remains elusive. Here we report the role of histone homocysteinylation in neural tube closure (NTC). A total of 39 histone homocysteinylation sites are identified in samples from human embryonic brain tissue using mass spectrometry. Elevated levels of histone KHcy and H3K79Hcy are detected at increased cellular Hcy levels in human fetal brains. Using ChIP-seq and RNA-seq assays, we demonstrate that an increase in H3K79Hcy level down-regulates the expression of selected NTC-related genes including Cecr2, Smarca4, and Dnmt3b. In human NTDs brain tissues, decrease in expression of CECR2, SMARCA4, and DNMT3B is also detected along with high levels of Hcy and H3K79Hcy. Our results suggest that higher levels of Hcy contribute to the onset of NTDs through up-regulation of histone H3K79Hcy, leading to abnormal expressions of selected NTC-related genes.

The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.

Silver nanoparticle (nAg), which is one of the most common manufactured nanomaterials, has a wide range of biomedical applications. The human oncogenic γ-herpesviruses, Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr Virus (EBV), are etiologically linked to many malignancies. Currently, there are no efficient or specific treatments for these types of tumors, and most patients die because of resistance to conventional cytotoxic chemotherapy. Despite nAg having antitumor and antiviral activities, its effects on oncogenic herpesvirus-related cancer cells remain largely unknown. Here, we reveal that nAg presents higher cytotoxicity against KSHV- or EBV-latently infected cells via reactivating viral lytic replication, which relies on the induction of reactive oxygen species (ROS) generation and autophagy. Moreover, nAg blocks KSHV primary infection by directly destroying virion particles, as well as effectively inhibits colony formation and moderately represses the growth of KSHV-associated tumors in xenograft mouse model. Taken together, these results demonstrate the therapeutic potential of nAg for use in the antiviral infection and treatment of oncogenic herpesvirus-related cancers.

Our data provide complementary insights for potential mechanisms of maternal diabetes induced NTDs.