Kruk, M. | bioRxiv Science

bioRxiv2024

TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation

Ten-Eleven Translocation (TET1-3) dioxygenases oxidize 5-methylcytosine (5mC) in DNA to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), initiating DNA demethylation. The three proteins share significant sequence homology and catalyze the same chemical reaction utilizing alpha-ketoglutarate cofactor and non-heme iron to oxidize the methyl group of 5mC. Since their discovery in 2009, there have been contradictory reports regarding the roles of TET proteins in cancer. TET genes have been characterized as tumor suppressor genes because their expression levels are reduced in many human cancers including lymphoma, prostate, and pancreas, and TET2 gene mutations are common in hematological cancers. However, TET1 was recently reported to be overexpressed in triple negative breast cancer and to act as a protooncogene in lung cancer. In the present study, we employed genetic approaches to directly address the function of TET1 protein in lung adenocarcinoma. We found that overexpression of TET1 in human lung adenocarcinoma (H441) cells decreased their proliferation and inhibited colony formation, cell migration, and 3D spheroid tumorigenesis. In contrast, TET1 knockout in lung adenocarcinoma accelerated cell growth and promoted colony formation, cell migration, and 3D spheroid tumorigenesis. Transcriptomics and proteomics analyses revealed that TET1 overexpression was associated with overexpression of immune markers, primarily via activation of TNF and NF-kB signaling pathways. TET1 knockout in lung adenocarcinoma cells induces the expression of genes involved in cellular metabolism and cell growth. Our results are consistent with a tumor suppressor role of TET1 gene in lung adenocarcinoma and reveal its role in activating antitumor immunity.

cancer biology↗

bioRxiv2023

Mother-Infant Gut Viruses and their Bacterial Hosts: Transmission Patterns and Dynamics during Pregnancy and Early Life

Early development of the gut ecosystem is crucial for lifelong health. While infant gut bacterial communities have been studied extensively, the infant gut virome remains under-explored. We longitudinally assessed the composition of gut viruses and their bacterial hosts in 322 total metagenomes and 205 metaviromes from 30 mothers during and after pregnancy and from their 32 infants during their first year of life. While the maternal gut virome composition remained stable during late pregnancy and after birth, the infant gut virome was dynamic in the first year of life and contained a higher abundance of active temperate phages compared to the maternal gut viromes. The infant gut virome composition was also influenced by infant feeding mode and place of delivery. Lastly, we provide evidence of viral-bacterial strains co-transmission from mothers to infants, demonstrating that infants acquire some of their virome from their mothers gut. Highlights- Longitudinal characterisation of the gut microbiome and virome in 30 mothers during pregnancy, at birth and 3 months after birth and in 32 infants from birth across the first year of life. - The maternal gut bacteriome changes from the first to the second trimester and then remains stable through birth and the first 3 months after birth. - The maternal gut virome remains stable during late pregnancy, birth and the first 3 months after birth. - The infant gut virome is highly dynamic during the first year of life and is shaped by infant feeding mode and place of delivery. - The infant gut harbours more temperate bacteriophages than the maternal gut, but their relative abundance decreases with increasing infant age. - Gut viral strains and their bacterial host strains are co-transmitted from mothers to their infants. - Gut viral strains are transferred from mother to infant around birth directly or via transfer of their bacterial hosts followed by the induction of prophages.

microbiology↗