Biology subjects

Johnston, H.

Publications and source records attributed to Johnston, H..

3 recordsLinked to original sources

bioRxiv2020

DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity

ABSTRACTDysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.SIGNIFICANCE We show that DGAT1 is a bona fide oncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Regeneration is a partial redeployment of the embryonic gene network

For over a century, researchers have been trying to understand the relationship between embryogenesis and regeneration. A long-standing hypothesis is that biological processes implicated in embryonic development are re-deployed during regeneration. In the past decade, we have begun to understand the relationships of genes and their organization into gene regulatory networks (GRN) driving embryonic development and regeneration in diverse taxa. Here, we compare embryonic and regeneration GRNs in the same species to investigate how regeneration re-uses genetic interactions originally set aside for embryonic development. Using a well-suited embryonic development and whole-body regeneration model, the sea anemone Nematostella vectensis, we show that at the transcriptomic level the regenerative program partially re-uses elements of the embryonic gene network along with a small cohort of genes that are specifically activated during the process of regeneration. We further identified co-expression modules that are either i) highly conserved between these two developmental trajectories and involved in core biological processes (e.g., terminal differentiation) or ii) regeneration specific modules that drive cellular events, such as apoptosis, that are unique to regeneration. Our global transcriptomic approach suggested that regeneration reactivates embryonic gene modules following regeneration-specific network logic. We thus verified this observation by functionally dissecting the role of MEK/ERK signaling during regeneration and established a first blueprint of the regeneration MEK/ERK-dependent GRN in Nematostella. Comparing the latter to the existing GRN underlying embryogenic development of the same species, we show at the network level that i) regeneration is a partial redeployment of the embryonic GRN, ii) embryonic gene modules are rewired during regeneration and iii) they are interconnected to novel down-stream targets, including "regeneration-specific" genes. Significance statementIn this intra-species transcriptomic comparison of embryonic development and regeneration in a whole-body regeneration model, the sea anemone Nematostella vectensis, we identified that 1) regeneration is a transcriptionally modest event compared to embryonic development and 2) that although regeneration re-uses embryonic genetic interactions, it does so by using regeneration specific network logic. In addition to identifying that apoptosis is a regeneration-specific event in Nematostella, this study reveals that GRN modules are reshuffled from one developmental trajectory to the other, even when accomplishing the same task (e.g. forming a fully functional organism). These findings highlight the plasticity of network architecture and set the basis for determining and functionally dissecting regeneration-inducing regulatory elements. From an evolutionary perspective, our study sets the foundation for further comparative work and provides new opportunities to understand why certain organisms can regenerate while others cannot.

developmental biology↗

bioRxiv2018

NvERTx: A gene expression database to compare Embryogenesis and Regeneration in the sea anemone Nematostella vectensis

For more than a century researchers have been comparing embryogenesis and regeneration hoping that lessons learned from embryonic development will unlock hidden regenerative potential. This problem has historically been a difficult one to investigate since the best regenerative model systems are poor embryonic models and vice versa. Recently however, the comparison of embryogenesis and regeneration has seen renewed interest as emerging models including the sea anemone Nematostella vectensis have allowed researchers to investigate these processes in the same organism. This interest has been further fueled by the advent of high-throughput transcriptomic analyses that provide virtual mountains of data. Unfortunately much of this data remains in raw unanalyzed formats that are difficult to access or browse. Here we present Nematostella vectensis Embryogenesis and Regeneration Transcriptomics - NvERTx, the first platform for comparing gene expression during embryogenesis and regeneration. NvERTx is comprised of close to 50 RNAseq datasets spanning embryogenesis and regeneration in Nematostella. These data were used to perform a robust de novo transcriptome assembly which users can search, BLAST and plot expression of multiple genes during these two developmental processes. The site is also home to the results of gene clustering analyses, to further mine the data and identify groups of co-expressed genes. The site can be accessed at http://nvertx.kahikai.org.

developmental biology↗