Biology subjects

Dephoure, N.

Publications and source records attributed to Dephoure, N..

3 recordsLinked to original sources

bioRxiv2018

Predicting peptide presentation by major histocompatibility complex class I using one million peptides

Improved computational tools are needed to prioritize putative neoantigens within immunotherapy pipelines for cancer treatment. Herein, we assemble a database of over one million human peptides presented by major histocompatibility complex class I (MHC-I), the largest known database of its type. We use these data to train a random forest classifier (ForestMHC) to predict likelihood of MHC-I presentation. The information content of features mirrors the canonical importance of positions two and nine in determining likelihood of binding. Our random forest-based method outperforms NetMHC and NetMHCpan on test sets, and it outperforms both these methods and MixMHCpred on new mass spectrometry data from an ovarian carcinoma sample. Furthermore, the random forest scores correlate monotonically with peptide binding affinities, when known. Finally, we examine the effect size of gene expression on peptide presentation and find a moderately strong relationship. The ForestMHC method is a promising modality to prioritize neoantigens for experimental testing in immunotherapy.

bioinformatics↗

bioRxiv2017

mTORC1 activates PASK-Wdr5 signaling to epigenetically connect the nutrient status with myogenesis.

In the tissue microenvironment, stem cell functions are modulated by extrinsic signaling cues such as peptide hormones and dietary nutrients. These signaling cues maintain the balance between self-renewal and differentiation of its resident stem cells. The mechanistic Target of Rapamycin Complex 1 (mTORC1) is implicated to play an important role in regulating this balance, although its downstream effectors in stem cells have been elusive. We have recently shown that the PASK protein kinase phosphorylates Wdr5 to stimulate muscle stem cell differentiation by epigenetically activating the Myogenin promoter. Here, we show that the PASK-Wdr5 signaling pathway is a nutrient-sensitive downstream target of mTORC1 in muscle stem cells. We show that phosphorylation of PASK, and in turn of Wdr5, by mTORC1 is required for the activation of Myogenin transcription, exit from the self-renewal and induction of the myogenesis program. Thus, mTOR connects the diverse extrinsic signaling cues to a central epigenetic process to regulate the muscle stem cell fate between self-renewal and differentiation.

cell biology↗

bioRxiv2017

A conserved signaling network monitors delivery of sphingolipids to the plasma membrane in budding yeast

In budding yeast, cell cycle progression and ribosome biogenesis are dependent upon plasma membrane growth, which ensures that events of cell growth are coordinated with each other and with the cell cycle. However, the signals that link the cell cycle and ribosome biogenesis to membrane growth are poorly understood. Here, we used proteome-wide mass spectrometry to systematically discover signals associated with membrane growth. The results suggest that membrane trafficking events required for membrane growth generate sphingolipid-dependent signals. A conserved signaling network plays an essential role in signaling by responding to delivery of sphingolipids to the plasma membrane. In addition, sphingolipid-dependent signals control phosphorylation of protein kinase C (Pkc1), which plays an essential role in the pathways that link the cell cycle and ribosome biogenesis to membrane growth. Together, these discoveries provide new clues to how growth-dependent signals control cell growth and the cell cycle.

cell biology↗