The Benefits of Middle Age

Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.

Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.

Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.

benefits-midage

They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!

Amy Lee Joins Biology Faculty

On August 1, Amy Lee joined the Biology department as an Assistant Professor. Previously, Amy was an American Cancer Society Postdoctoral Scholar in Jamie Cate’s lab at University of California, Berkeley. She received her Ph.D. in Virology from Harvard University in Sean Whelan’s lab and her Bachelors of Science in Biology from Massachusetts Institute of Technology.

Stx.key

eIF3d structure, see Figure 2 at http://rdcu.be/jzDD

Amy’s research focuses on understanding how gene regulation shapes cell growth and differentiation, and how dysregulation leads to human diseases like carcinogenesis and neurodegeneration. She is interested in discovering new mechanisms of mRNA translation initiation and novel functions of RNA-binding proteins and eukaryotic translation factors. Her research combines genome-wide and computational approaches together with molecular genetics, cell biology, biochemistry, and structural biology techniques.

Amy recently published a paper in Nature together with the Jamie Cate, Jennifer Doudna, and Philip Kranzusch describing the discovery of a new translation pathway that controls the production of proteins critical to regulating the growth and proliferation of cells. Cancer is characterized by uncontrolled cell growth, which means the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists for decades have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein. One key insight more than 40 years ago was that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eIF4E (eukaryotic initiation factor 4E) for all mRNAs.

Amy and her colleagues discovered that for a certain specialized subset of mRNAs – most of which have been linked somehow to cancer – initiation is triggered by a different protein, called eIF3d. The finding was a surprise because the protein is part of an assembly of 13 proteins called eIF3 -eukaryotic initiation factor 3 – that has been known and studied for nearly 50 years, and no one suspected its undercover role in the cell. This may be because eIF3’s ability to selectively control mRNA translation is turned on only when it binds to the set of specialized mRNAs. Binding between eIF3 and these mRNAs opens up a pocket in eIF3d that then latches onto the end-cap of mRNA to trigger the translation process. Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA tag and which open up the cap-binding pocket. eIF3d thus presents a promising new drug target in cancer, as a drug blocking this binding protein could shut off translation of only the growth-promoting proteins and not other life-critical proteins inside the cell.

Lee AS, Kranzusch PJ, Doudna JA, Cate JH. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature. 2016.

 

Yoshinori Ohsumi to Receive Rosenstiel Award Wednesday, April 6

ohsumi220Biologist Yoshinori Ohsumi will receive the 45th Rosenstiel Award for Distinguished Work in Biomedical Science this Wednesday, April 6th at 4:00 pm in Gerstenzang 123. At that time, he will present a lecture titled, “Lessons from yeast: Cellular recycling system, autophagy”.

Ohsumi is a cell biologist and professor at the Tokyo Institute of Technology’s Frontier Research Center in Japan. He is one of leading experts in the world on autophagy, a process that allows for the degradation and recycling of cellular components. The Rosenstiel Award is being given to Ohsumi in recognition of his pioneering discoveries in autophagy.

Learn more about Professor Ohsumi and his research at BrandeisNow.

SPROUT Continues Growing Support for Brandeisian Innovators

Lil_Sprout_smallProgram Will Bestow Up to $100,000 to Promising Research Proposals

Could your research impact the world or do you have an idea that could create positive change? Need funding? SPROUT can help with that.

The popular SPROUT program, now in its sixth year, has announced increased funding for the 2016 round of proposals. SPROUT is funded by the Office of the Provost and run by Office of Technology Licensing. This year the Hassenfeld Family Innovation Center, recently created to support entrepreneurial and innovative collaborations happening across campus, contributed an additional $50,000 to be disbursed among the most promising requests.

Historically, the program has supported a diverse scope of lab-based innovations from all departments in the sciences  including Biology, Biochemistry, Physics, and Chemistry.  Past candidates have proposed projects ranging  from early‐stage research and development to patent‐ready projects ranging from treatments for diseases to lab tools.  Brandeis lab scientists have pitched their projects, including HIV vaccines (Sebastian Temme, Krauss lab),  neuroslicers (Yasmin Escobedo Lozoya, Nelson lab) and the use of carrot fiber as an anti-diabetic  (Michelle Landstrom, Hayes lab) to a panel of distinguished, outside judges. A SPROUT award can jumpstart your innovation and lead to continued opportunities. SPROUT awardees researching the use of carrot fiber as an anti-diabetic food agent were just awarded additional funding by the Massachusetts Innovation Commercialization Seed Fund program.

Other successful projects include “Enzymatic Reaction Recruits Chiral Nanoparticles to Inhibit Cancer Cells” led by Xuewen Du from the Xu lab, “Semaphorin4D: a disease‐modifying therapy for epilepsy” led by Daniel Acker of the Paradis lab, “X‐ray transparent Microfluidics for Protein Crystallization” led by Achini  Opathalage from the Fraden lab and “New and Rational Catalyst Development for Green Chemistry”  from the Thomas lab.  Those interested in learning more about past SPROUT winners are invited to read this recent Brandeis NOW article. A list of additional winners, along with their executive summaries, is available on the Brandeis OTL website.

Teams seeking support for scientific projects which require bench research, lab space, and/or lab equipment are encouraged to submit an abstract prior to the March 7 deadline. The competition is open to the entire Brandeis community including faculty, staff, and students. The Office of Technology Licensing will conduct information sessions on Thursday, February 25th 11:30 a.m.‐12:30 p.m. in Volen 201 and on Monday, February 29th 1:00 p.m.‐2:00 p.m. at the Shapiro Science Center, 1st Floor Library. Staff will address the application process as well as specific questions and interested applicants are highly encouraged to attend.

More details regarding the SPROUT awards, process and online application may be found at bit.ly/SPROUT16.

Symposium Celebrating Ranjan Sen to be held January 30, 2016

senThe Biology department is cosponsoring an all-day symposium “Cellular and Molecular Immunology in Health and Disease” on Saturday, January 30. The symposium will be held in Gerstenzang 121 from 8:30 am to 6:00 pm. This symposium celebrates Ranjan Sen’s 60th birthday and is organized by Sen’s Brandeis alumni.  This symposium is open to the public, although the breakfast and lunch are by invitation only and are not open to the public.

The list of speakers includes:

  • Sen_Symposium_2016_FINALFredrick Alt, Ph.D., Harvard Medical School
  • Dipanjan Chowdhury, Ph.D., Harvard Medical School
  • David Schatz, Ph.D., Yale School of Medicine
  • Stephen Desiderio, M.D., Ph.D., John Hopkins Medicine
  • Sankar Ghosh, Ph.D., Columbia University
  • Barbara Nikolajczyk, Ph.D., Boston University
  • Stephen Smale, Ph.D., University of California, Los Angeles
  • Joel Pomerantz, Ph.D., Johns Hopkins University School of Medicine
  • Rudolf Grosschedl, Ph.D., Max Planck Institute, Germany
  • Batu Erman, Ph.D., Sabanci University, Turkey
  • Christina Jamieson, Ph.D., University of California, San Diego, School of Medicine
  • Yehudit Bergman, Ph.D., The Hebrew University of Jerusalem, Israel

More information about this event is available.

 

FOXO links stress to the innate immune response in flies

Life is tough. Every living thing is constantly dealing with insults that damage or disrupt homeostasis. At the cellular level these insults, or stresses, come in multiple forms: starvation, oxidative stress, heat shock, radiation damage, and infection. In response to these stresses, organisms have evolved numerous mechanisms to promote survival. Broadly speaking, an insult stimulates various signaling cascades that alter gene expression in the cell.

One way this is achieved is through the “turning on” of transcription factors. One such transcription factor is FOXO, which is activated under many types of stress, both metabolic and environmental. Another way gene expression can be accomplished is the post-transcriptional control of gene expression. An important player of post-transcriptional control is the small RNA pathways composed of the RNA interference (RNAi), micro RNA (miRNA), and PIWI RNA (piRNA) branches. In a recent article from the Marr lab titled “FOXO regulates RNA interference in Drosophila and protects from RNA virus infection”, published in PNAS this November, the authors identify a new connection between both the transcriptional and small RNA mediated post-transcriptional mechanisms that respond to stress.

Screen Shot 2015-11-16 at 9.22.43 AM

RNAi efficiency is enhanced in a dFOXO-dependent manner. For full explanations, see Fig. 2 in Spellberg & Marr (2015)

Using Drosophila as a model system, the authors identify FOXO as a transcription factor that regulates important genes in the small RNA pathways in response to stress. This is the first transcription factor identified to control these genes. Despite being a hot and competitive field for over 15 years, work in small RNA pathways had yet to reveal the transcriptional regulation of the core protein machinery that are involved in small RNA biogenesis and utilization. Under stress conditions, FOXO directly binds the promoters of core small RNA pathway genes, such as Ago1, Ago2, and Dicer 2, leading to increases in their expression. As one might expect, this is followed by an increase in RNAi efficiency and post-transcriptional control of gene expression.

A known physiological role for RNAi is to fight off viral infections as part of an innate immune response. The authors find that FOXO is activated by viral infection to promote this anti-viral response. In addition, animals deleted for the FOXO gene are more susceptible to a viral infection. Theses results are consistent with the notion that virally-activated FOXO stimulates RNAi gene transcription as a mechanism to enhance viral immunity.

Finally, the work in this paper identifies integration between metabolic and stress signaling and the innate immune response, with FOXO serving the bridge. There is evidence that acute stress can confer a protective effect against infection in humans. If the identified role of FOXO is conserved, perhaps it can be utilized therapeutically.

Spellberg MJ, Marr MT, 2nd. FOXO regulates RNA interference in Drosophila and protects from RNA virus infection. Proc Natl Acad Sci U S A. 2015

DUB inhibitors _or_ why you should you eat your broccoli

Eat your broccoli!

We’re constantly bombarded by advice on which foods to eat or not eat, but skeptics among us often find compelling evidence for a convincing mechanism of how the foods promote health hard to come by – food has many components, and there are many different cells and metabolic pathways in those cells with which those components interact.

phenethyl isothiocyanate (a component of cruciferous vegetables)

phenethyl isothiocyanate (PEITC, a component of cruciferous vegetables)

Consider broccoli. It is well established that cruciferous vegetables have wide-ranging health benefits, apparently reducing cancer risks and lowering inflammation.  One set of phytochemicals responsible for the potent anti-cancer and anti-inflammatory properties are called isothiocyanates or ‘ITCs’.  It is now four decades since the discovery of ITCs, yet a molecular understanding of what ITCs do in a cell has proven elusive.

In a paper published this month in Cancer Research, Brandeis research scientist Ann Lawson, working in Liz Hedstrom’s laboratory, together with graduate students Marcus Long (Biochem) and Rory Coffey (Mol Cell Biol) and scientists from UbiQ and from Boston College, has shown that ITCs block the action of deubiquitinating enzymes (DUBs),  including the tumorigenesis-associated enzymes USP9x and UCH37, at physiologically relevant concentrations and time scales.

DUB inhibition provides a simple, unifying explanation that can account for many of the diverse health effects of ITCs. Understanding of how ITCs work at the molecular level may, one day, lead to new drug therapies for illnesses such as cancer, chronic inflammation, and neurodegenerative diseases.

Are you ready for your broccoli now? Me, I think I’ll have some kale sprouts.

Lawson AP, Long MJ, Coffey RT, Qian Y, Weerapana E, El Oualid F, Hedstrom L. Naturally occurring isothiocyanates exert anticancer effects by inhibiting deubiquitinating enzymes. Cancer Res. 2015

Gio Biosco (P’98) gets NIH Pioneer Award

Molecular and Cell Biology alum Giovanni Bosco Giovanni Bosco Ph.D. ’98, currently Associate Professor of Genetics at Dartmouth, recently received a Pioneer Award from the NIH.

Gio Bosco is a die-hard chromatin regulation guy who became interested in whether long-term changes in DNA structure are involved in long-term behavioral plasticity. Gio did his PhD work in Jim Haber’s lab and provided some of the earliest and strongest evidence for a critical DNA repair mechanism called break-induced replication, which plays an essential role in maintaining the integrity of chromosome ends when the normal end-addition of DNA by telomerase is absent.

In his postdoctoral work, Giovanni turned from using yeast as a model system to Drosophila.  In the lab of Terry Orr-Weaver at MIT he focused his attention on the role of DNA replication in regulating gene amplifications and became interested in the importance of post-translational modifications (acetylations and phosphorylations) of the histone proteins that wrap the DNA into chromatin.

Approximately 7 years ago Gio started contemplating the question of how these post-translational histone modifications change during behavior and learning. He returned to his Brandeis roots to develop tools and approaches to address this problem. He received an NIH K18 grant to fund a sabbatical in Leslie Griffith’s lab in 2010. He and his behavior group have remained connected to Brandeis since then through frequent joint group meeting visits.

We’ll be interested to hear more about the role of histone modifications in how learning and memory occurs in the context of social behavior, and in how social behavior can be inherited through multiple generations, as the result of the Bosco lab research funded by this award.

 

Protected by Akismet
Blog with WordPress

Welcome Guest | Login (Brandeis Members Only)