Project description:The RNA-binding protein Snd1 can regulate gene expression through various mechanisms, including microRNA decay. Here we have investigated microRNA expression in livers of WT and Snd1 knockout (KO) mice
Project description:Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that “reads” methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. SND1 is a known driver of hepatocellular carcinoma, but it is unknown if the Tudor domain is needed to drive this disease. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings. To do so, we developed two genetically engineered SND1 mouse models, namely a knockout (Snd1 KO) and a Snd1 Tudor domain mutated (Snd1 KI) mouse. Transcriptome analysis of normal KO and KI liver samples reveals a role for the SND1 Tudor domain in regulating expression of major acute phase proteins (APPs) and genes involved in the unfolded protein response (UPR), which could provide mechanistic insight into SND1’s functions in a tumor setting. These processes may provide insight into how SND1 functions as an oncogene. These results support the use of PRMT5 inhibitors, and the development of small molecule inhibitors that target the SND1 Tudor domain, as novel treatments for HCC.
Project description:PyMT tumor cells with indicated status of Mtdh and Snd1 were treated with camptothecin (CPT) and the transcirptome profiles were determined and compared two sets of experiments: (1) vector control vs Snd1-KD under CPT treament (2) PyMT/Mtdh-KO cells reconstituted with either WT or Snd1-binding deficient mutant Mtdh (W391D) under CPT treatment
Project description:Staphylococcal nuclease and tudor domain containing protein 1 (SND1), which is also known as p100 or Tudor-SN, is a recently identified protein that is highly expressed in multiple cancers including breast cancer, liver cancer, and colon cancer. Endothelial function and vascular integrity are critical modulators in cancer metastasis and progression. Although much progress has been made in studying SND1’s oncogenic role, the involvement of SND1 in endothelial function has never been explored.
Project description:The pancreatic β cell synthesizes, packages, and secretes insulin in response to glucose-stimulation to maintain blood glucose homeostasis. Under diabetic conditions, a subset of β cells fail and lose expression of key transcription factors (TFs) required for insulin secretion. Among these TFs is Pancreatic and duodenal homeobox 1 (Pdx1), which recruits a unique subset of transcriptional coregulators to modulate its activity. Here we describe a novel interacting partner of Pdx1, the Staphylococcal Nuclease and Tudor domain-containing protein (Snd1), which has been shown to facilitate protein-protein interactions and transcriptional control through diverse mechanisms in a variety of tissues. Pdx1:Snd1 interactions were confirmed in rodent β cell lines, mouse islets and human islets. Utilizing CRISPR-Cas9 gene editing technology, we deleted Snd1 from the mouse β cell lines, which revealed numerous differentially expressed genes linked to insulin secretion and cell proliferation, including limited expression of Glp1r. We observed Snd1 deficient β cell lines had reduced cell expansion rates, Glp1r protein levels and limited cAMP accumulation under stimulatory conditions, and further show that acute ablation of Snd1 impaired insulin secretion in rodent and human β cell lines. Lastly, we discovered that PDX1:SND1 interactions were profoundly reduced in human β cells from donors with type 2 diabetes (T2D). These observations suggest the Pdx1:Snd1 complex formation is critical for controlling a subset of genes important for β cell function and is targeted in diabetes pathogenesis