Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions, and its mis-regulation is linked to cancer development. New work from the Shi lab, published in Molecular Cell (see also the Preview in the same issue), showed that, in mESCs, the Polycomb repressive complex 2 (PRC2)-associated protein EPOP/C17orf96 co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly upregulated in human cancer, and its loss impairs the proliferation of several human cancer cell lines. These findings establish EPOP as a transcriptional modulator, which impacts both Polycomb and active gene transcription in mammalian cells, and a possible involvement of EPOP in human cancerogenesis.
The Cell Biology Microscopy Facility (CBMF) is proud to announce that their new lattice light sheet microscope is up and running! This state-of-the art instrument, designed by the lab of Nobel Prize winner Eric Betzig (Janelia Research Campus), provides unprecedented spatiotemporal resolution for imaging live samples in 3-D over time, while minimizing photo-toxicity and photobleaching. We invite you to check it out! Thanks to Talley Lambert of the CBMF for all his work in bringing this instrument to life!
Mutations in mitochondrial proteins (either nuclear or mitochondrial-encoded) cause bioenergetic failures observed in mitochondrial diseases. Rescue of these bioenergetic defects constitutes a feasible strategy to prevent cellular deterioration that leads to cell death. New work from the Puigserver lab, published in Molecular Cell (see also the Preview in the same issue), reports that bromodomain inhibition or loss of Brd4 correct bioenergetic deficiency caused by mitochondrial disease complex I mutations. Using chemical and genome-wide CRISPR editing screens in complex I trans-mitochondrial hybrids cells, they find that chemical inhibition or loss of Brd4 rescue cell death caused by growth under conditions requiring oxidative phosphorylation for survival. Mechanistically, Brd4 controls a set of mitochondrial genes that bypass complex I mutations rewiring the electron transfer chain through complex II. These studies provide a metabolic/energetic strategy to overcome cellular failure caused by defects in mitochondrial complex I.
Congratulations to Steve Liberles! He recently was named an HHMI Faculty Scholar as an early career scientist with great potential. These scholar awards are funded by the Howard Hughes Medical Institute (HHMI), the Simons Foundation, and the Bill & Melinda Gates Foundation. For more information, see here. Additionally, Steve was awarded an NIH Pioneer Award. For more information, see here.
How the shape of an organelle is generated is only poorly understood, but is a fundamental question in cell biology. An interesting example is the endoplasmic reticulum (ER) as it consists of morphologically distinct domains. The ER comprises the nuclear envelope and the peripheral ER that consists of tubules connected by three-way junctions into a network, as well as interdispersed sheets. During mitosis, the tubular ER network converts into sheets. Two protein families, the reticulons (Rtns) and DP1 stabilize the high membrane curvature of tubules in cross-section. Fusion is mediated by membrane-bound GTPases of the dynamin family, called atlastins (ATLs) in metazoans. A third protein, termed lunapark, is reported to be involved in ER morphology and its exact role is unknown. Work from the Rapoport Lab, published in eLife, has elucidated the interrelationship between ATL, Rtns/DP1, and Lnp, using mammalian cells and frog egg extracts. Surprisingly, ATL is not only required to form an ER network, but also to maintain it. A balance between ATL and Rtn activity is needed for network maintenance; high concentrations of Rtn disassemble the ER into vesicles, but this can be reversed by increasing the concentration of ATL. The results suggest a model in which ATL tethers and fuses tubules stabilized by Rtns. Lnp subsequently moves into three-way junctions and probably stabilizes them. Loss-of-function of Lnp in both mammalian cells and frog egg extracts leads to the expansion of peripheral sheets. During mitosis, Lnp is phosphorylated and inactivated, suggesting that Lnp may contribute to the characteristic tubule-to-sheet transition of the ER.
(A) A tubular ER network was assembled from the interphase frog egg extracts.
(B) The addition of a cytosolic fragment of Lnp into the frog egg extracts converted the tubular ER network into sheets.
Metabolic reprogramming in cancer cells is tightly associated with tumor progression but the effect of metabolic regulatory circuits on metastasis processes is poorly understood. New work from the Puigserver lab, published in Nature, reports that mitochondrial heterogeneity driven through the transcriptional coactivator PGC1a defines populations of melanoma cells with different metastatic capacity. Mechanistically, a PGC1a transcriptional axis suppresses a subset of integrin genes that are known to influence invasion and metastasis. This axis is the target of BRAF inhibitors that independently of its cytostastic effects suppress metastasis through integrin signaling. Thus, PGC1a -mediated mitochondrial heterogeneity is important during melanoma progression changing in response to different signals including nutrients, and switching between survival-proliferation and invasion-metastasis.
John Flanagan is one of four researchers who have won this year’s António Champalimaud Vision Award, which recognizes their groundbreaking research into the connection between the eyes and the brain and its implications for novel vision therapies. First awarded in 2007, the António Champalimaud Vision Award is supported by the World Health Organization and the International Agency for the Prevention of Blindness’ Vision 2020 - The Right to Sight global initiative. This award was covered by the Associated Press and the New York Times. Congratulations, John!
Axonal degeneration is frequently observed before the death of neuronal cell bodies in patients with neurodegenerative disorders including ALS and contributes significantly to neurological disability. While blocking axonal degeneration may represent an important therapeutic goal, the mechanism of axonal degeneration is unclear. In a recent paper published in Science by Yuan lab, Ito et al. investigated the role of RIPK1 in Optn-/- mice. Loss-of-function mutations in the Optineurin (Optn) gene have been implicated in both familial and sporadic cases of ALS. The authors demonstrated that optineurin actively suppressed RIPK1-dependent signaling by regulating its turnover. Loss-of-Optn led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery, including RIPK1, RIPK3 and MLKL, in the CNS. Furthermore, RIPK1/RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS. Thus, RIPK1/RIPK3 plays a critical role in mediating progressive axonal degeneration and inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.
To initiate an immune response against pathogens, a small number of T cells within the polyclonal repertoire need to proliferate rapidly to generate large numbers of effector cells that can clear pathogens. To generate the precursors required for macromolecular synthesis, energy and stress response, the T cells activate anabolic metabolism that is coupled with increased mitochondrial mass. In a recent publication in Cell Metabolism, the Haigis Lab uses T cell activation to address a fundamental question in mitochondrial biology: Does biogenesis merely replicates existing mitochondria, or generates a distinct population of mitochondria with specialized functions? Noga Ron-Harel and co-workers, in collaboration with the Gygi and Sharpe labs, show that naïve T cell activation induces a unique program of synchronized mitochondrial biogenesis and proteome remodeling, giving rise to mitochondria with a distinct proteomic signature that drives one-carbon (1C) metabolism. They demonstrate for the first time that mitochondrial 1C metabolism is important for de-novo purine biosynthesis and redox control in T cells. Genetic inhibition of mitochondrial 1C metabolism impaired antigen-specific T cell proliferation and survival in vitro and in vivo. In sum, this study identifies 1C metabolism as an early and essential metabolic signature of naïve T cell activation, and shows that mitochondrial proliferation gives rise to a new population of organelles with distinct and specialized functions.
The vagus nerve is a key body-brain connection that monitors the respiratory, cardiovascular, and digestive systems. Within the gastrointestinal tract, vagal sensory neurons detect a diversity of stimuli including nutrients, nausea-inducing toxins, and mechanical stretch of the stomach and intestine. In a recent publication in Cell, the Liberles Lab identified two classes of vagal gut-to-brain neurons that exert powerful and opposing effects on digestion. Genetically guided anatomical mapping reveals that vagal GPR65 neurons densely innervate intestinal villi near the pyloric sphincter, vagal GLP1R neurons instead target the stomach, and both neuron types innervate dedicated brainstem subnuclei. Optogenetic stimulation of vagal GPR65 neurons selectively blocks gastric contractions without impacting breathing or heart rate, and in vivo ganglion imaging reveals that GPR65 and GLP1R neurons differentially respond to intestinal food and stomach stretch. Delineating gut-to-brain sensory neurons provides a needed foundation for understanding neural control of gastrointestinal physiology.