Molecular Neurobiology and RNA metabolism
Our laboratory is interested for understanding how molecular processes in the brain determine behavior with special emphasis on RNA metabolism. We are particularly interested on the role of circular RNAs (circRNAs) at the molecular and neural levels as well as the mechanisms underlying circadian clocks.
Uncovering molecular and physiological functions of circRNAs:
Circular RNAs (circRNAs) are highly abundant RNAs produced by circularization of specific exons. Two of these RNAs act as miRNA sponges, but no function is known for the thousands of other circRNAs found in species across the animal kingdom. CircRNAs expression levels are not correlated with the expression of their linear isoforms, indicating a potentially widespread layer of previously unknown gene regulation. Further, our work and that of others has suggested functions of these molecules in vivo. For example, we showed that circRNA biogenesis competes with canonical splicing, showing that circRNAs can function in cis as “RNA traps”. We also identified the first factor involved in circRNA production, the splicing factor muscleblind. Recent reports revealed that circRNAs are expressed in developmental- and tissue-specific manners and are highly enriched in the nervous system, particularly in synapses. Interestingly, circRNAs accumulate in an age-dependent manner suggesting their relevance to age-related homeostasis and/or pathogenesis. Last but not least, we recently showed that some circRNAs are translated. We showed that their translation is mediated by IRES-like sequences, is enhanced in response to starvation and happens in association with membranes and in synapses.
Now the stage is set for the most exciting questions, which we are currently working in the lab, by combining molecular, computational and RNA biology with advances techniques in genetics and neurosciences. These questions are:
- What are the functions of circRNAs in vivo?
- How do circRNAs work at the molecular level?
- What are the key functions of these molecules in the brain and during aging?
- How do circRNAs evolve?
- Are circRNAs involved in neurodevelopmental and neurodegenerative diseases?
A systemic view of circadian clocks.
Circadian clocks organize cellular, physiological, and behavioral timing in 24-hour cycles. Understanding how circadian rhythms are generated, maintained, and adapted to changing conditions is key, as several diseases such as cancer and depression are associated with misalignment of the circadian clock with the environment. The current model postulates that circadian oscillators keep time by complex transcriptional and post-transcriptional feedback loops. Circadian clocks are remarkably robust: they are able to keep time without timing cues and are resilient to large variations in environmental conditions. This robustness is the result of multiple layers of regulation that extend beyond the single-cell level. Circadian clocks are also exceptionally plastic as they can quickly and specifically adjust to specific environmental cues. This plasticity is the result of the existence of very efficient input pathways that convey the external signals into the core oscillator machinery.
Our lab is interested in determining how molecular and neural circadian components regulate each other and generate a system that is both robust and plastic. For doing this, we study the circadian clock from a systemic point of view, including studies at the molecular and neural levels. We showed that miRNAs have a key role in providing robustness to the circadian system both during development and in adults. Moreover, we also showed that the neural and molecular circadian systems compensate and interact with each other.
In this context, the most important question looking forward are:
- What is the contribution of non-coding RNAs (small and large) to the robustness of the circadian system? What is their mechanisms of action?
- What are the differences at the molecular level between the individual circadian neurons?
- What are the general mechanism of the circadian clock to deal with genetic and/or environmental perturbations?
- What are the neural and molecular basis of temperature adaptation and compensation?
- Zaffagni M, Kadener S. Craving for Introns. Mol Cell. 2019;73(6):1095-6.
- Simchovitz A, Hanan M, Niederhoffer N, Madrer N, Yayon N, Bennett ER, Greenberg DS, Kadener S, Soreq H. NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug-inducible neuroprotection from oxidative stress. FASEB J. 2019:fj201900830R.
- Patop IL, Wust S, Kadener S. Past, present, and future of circRNAs. EMBO J. 2019 Aug 15;38(16):e100836.
- Zhonghua Zhu, Tamara Sanchez Ortiz, Shaul Mezan, Sebastian Kadener, Justin Blau. Transcription of a plasticity gene is activated by neuronal hyperpolarization. bioRxiv 636878.
- Lauren Foley, Jinli Ling, Radhika Joshi, Naveh Evantal, Sebastian Kadener, Patrick EmeryPSI controls tim splicing and circadian period in Drosophila. bioRxiv 504282.
- Naveh Evantal, Ane Martin Anduaga, Osnat Bartok, Ines Lucía Patop, Ron Weiss, Sebastian KadenerThermosensitive alternative splicing senses and mediates temperature adaptation in Drosophila. bioRxiv 503409.
- Nagarjuna Reddy Pamudurti, Vinay Vikas Konakondla-Jacob, Aishwarya Krishnamoorthy, Reut Ashwal-Fluss, Osnat Bartok, Stas Wüst, Katerina Seitz, Roni Maya, Noam Lerner, Ines Lucia Patop, Silvio Rizzoli, Tsevi Beautus, Sebastian KadenerAn in vivo knockdown strategy reveals multiple functions for circMbl. bioRxiv 483271.
- Patop IL, Kadener S. circRNAs in Cancer. Curr Opin Genet Dev. 2018;48:121-7. PMCID: PMC5877416.
- Chatterjee A, Lamaze A, De J, Mena W, Chelot E, Martin B, Hardin P, Kadener S, Emery P, Rouyer F. Reconfiguration of a Multi-oscillator Network by Light in the Drosophila Circadian Clock. Curr Biol. 2018 Jul 9; 28(13): 2007–2017.e4.
- Wittenbrink N, Ananthasubramaniam B, Munch M, Koller B, Maier B, Weschke C, Bes F, de Zeeuw J, Nowozin C, Wahnschaffe A, Wisniewski S, Zaleska M, Bartok O, Ashwal-Fluss R, Lammert H, Herzel H, Hummel M, Kadener S, Kunz D, Kramer A. High-accuracy determination of internal circadian time from a single blood sample. J Clin Invest. 2018;128(9):3826-39. PMCID: PMC6118629.
- Levin-Klein R., Fraenkel S., Lichtenstein M., Matheson L., Bartok O., Nevo Y., Kadener S., Corcoran A., Cedar H., Bergman Y. “Clonally stable VK allelic choice instructs IgK repertoire”. Nature Comm. 8, 15575 (2017).
- Pamudurti N., Bartok O., Jens O., Ashwal-Fluss R., Stottmeister C., Ruhe L., Hanan M., Wyler E., Perez-Hernandez D., Ramberger E., Shenzis S., Samson M., Dittmar G., Landthaler M., Chekulaeva M., Rajewsky N. and Kadener S. “Translation of circRNAs”. Molecular Cell 66(1), 9-21 (2017).
- Featured in Molecular Cell 66(1), 1-2 (2017)
- Feature in Science 355 (6332), 1363 (2017).
- Featured in Nature Reviews Genetics 18, 272-273 (2017).
- Featured in Cell Research 27, 724-725 (2017)
Afik S. 1, Bartok O. 1, Artyomov M., Shishkin A., Kadri S., Zhu X., Gutman M., Garber M.* and Kadener S.* “Defining the 5’ and 3’ landscape of the Drosophila transcriptome with ExoCAGE and RNaseH-seq”. Nucleic Acids Research 47(11): e95; 1-16 (2017).
- Cohen-Hadad Y., Altarescu G., Eldar-Geva T., Levi-Lahad E., Zhang M., Rogaeva, E. Gotkine M., Bartok O., Ashwal-Fluss R., Kadener S., Epsztejn-Litman S., Eiges R. “Marked differences in C9orf72 methylation status and isoform expression between C9/ALS human embryonic and induced pluripotent stem cells”. Stem Cell Reports 8(7), 927-940 (2016).
- Mezan S., Feuz JD, Deplancke B. and Kadener S. “PDF signaling is an integral part of the Drosophila circadian molecular oscillator”. Cell Reports 17(3), 708-719 (2016).
- Hanan M., Soreq H. and Kadener S. “CircRNAs in the brain”. RNA Biology Nov28:1-7 (2016).
- Derr A, Yang C, Zilionis R, Sergushichev A, Blodgett DM, Redick S, Bortell R, Luban J, Harlan DM, Kadener S, Greiner DL, Klein A, Artyomov MN, Garber M. “End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data”. Genome Research 26(10), 1397-1410 (2016).
- Chikne V.*, Doniger T.*, Bartok O.*, Eliaz D.*, Cohen Chalamish S., Tschudi C., Unger R., Hashem Y., Kadener S. and Michaeli S. “Pseudouridylation in Trypanosoma brucei rRNA is developmentally regulated in positions critical for ribosome function”. Scientific Reports 6, 25296:1-13 (2016).
Tattikota SG., Rathjen T., Hausser J., Khedkar A., Kabra UD., Pandey V., Sury M., Wessels HH., Mollet IG., Eliasson L., Selbach M., Zinzen RP., Zavolan M., Kadener S, Tschöp MH, Jastroch M, Friedländer MR., Poy MN. “miR-184 regulates pancreatic β-Cell function according to glucose metabolism”. J. Biol. Chem. 290 (2015).
- Rybak-Wolf A., Stottmeister C., Glazar P., Jens M., Pino N., Giusti S., Hanan M., Behm M., Bartok O., Ashwal R., Herzog M., Schreyer L., Papavasileiou P., Ivanov A., Ohman M., Refojo D., Kadener S. and Rajewsky N. “Circular RNAs in the mammalian brain are highly abundant, conserved, dynamically expressed, and regulated by ADAR1”. Molecular Cell 58 (2015).
- Bartok O., Teesalu M., Pandey V., Hanan M., Poukkula M., Havula E., Moussaieff A., Vodala S., Nahmias Y., Kadener S.* and Hietakangas V.* “Cabut-dependent repressive branch of the sugar sensing transcriptional network regulates glyceroneogenesis”. * Corresponding authors. EMBO J. 34 (2015).
- Lerner I.*, Bartok O.*, Afik S., Menet J., Wolfson V., Weissbein U., Haimovich D., Gafni C., Friedman N., Rosbash M. and Kadener S. “Clk post-transcriptional control denoises circadian transcription in time and space”. Nature Communications 6 (2015).
- Stelzer Y., Bar S., Bartok O., Afik S., Ronen D., Kadener S.* and Benvenisty N.* “Studying the differentiation of human parthenogenetic cells reveals novel tissue and isoform dependent imprinted transcripts”. * Corresponding authors. Cell Reports11(2):308 (2015).
- Ashwal-Fluss R., Meyer M., Pamudurti N.R., Ivanov A., Bartok O., Evantal N., Hanan M., Memczak S., Rajewsky N.* and Kadener S.* “CircRNA biogenesis and canonical splicing compete with each other”. Molecular Cell 55:172 (2014).
- Featured in Cell, 159(1), October 2014.
- Featured in Nature Review Genetics, November 2014.
Selected for Faculty 1000.
- Weiss R., Bartok O., Mezan S., Malka Y and Kadener S. “Synergistic Interactions between the Molecular and Neuronal Circadian Networks Drive Behavioral Circadian Rhythms in Drosophila melanogaster”. PloS Genetics 10:e1004252 (2014).
- Mezan S., Ashwal-Fluss R., Shenhav R., Garber M. and Kadener S. “Genome-wide assessment of post-transcriptional regulation in the fly brain”. Frontiers in Molecular Neuroscience 6:49 (2013).
- Bartok O., Kyriacou C., Levine J., Sehgal A. and Kadener S. “Adaptation of molecular circadian clockwork to environmental changes: a role for alternative splicing and miRNAs”. Proc R. Soc. B. 280:2013001 (2013).
- Pandey V., Turm H., Bekenstein U., Shifman S. and Kadener S. “A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in PKAN pathogenesis”. Frontiers in Cell Neuroscience 7: 146 (2013).
- Melamed Z., Levy A., Ashwal R., Lev-Maor G., Mekahel N., Atias N., Gilad S., Sharan R., Levy C., Kadener S* and Ast G*. “Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions”. * Corresponding authors. Mol. Cell 50:869(2013).
- Belacortu Y., Weiss R., Kadener S. and Paricio N. “Transcriptional activity and nuclear localization of Cabut, the Drosophila ortholog of vertebrate TGF-β-inducible early-response gene (TIEG) proteins”. PLoS One 7(2):e32004 (2012).
- Belancortu Y., Weiss R., Kadener S. and Paricio N. “Expression of Drosophila cabut during early embryogenesis, dorsal closure and nervous system development”. Gene Expr Patterns 3-4: 190 (2011).
- Bekenstein U. and Kadener S. “What can Drosophila teach us about iron-accumulation neurodegenerative disorders?” J. Neural Trans 118(3):389 (2011).
- Van der Linden A.M., Beverly M., Kadener S., Rodriguez J., Wasserman S., Rosbash M. and Sengupta P. “Genome-Wide Analysis of Light and Temperature-Entrained Circadian Transcripts in C. elegans”. PLoS Biology 8(10):e10000503 (2010).
- Fathallah-Shaykh H.M., Bona J.L. and Kadener S. “Mathematical Model of the Drosophila Circadian Clock: Loop Regulation and Transcriptional Integration”. Biophys J. 97(9): 2399 (2009). Cover article. Selected for Faculty of 1000 (Factor 8 Must read)
- Kadener S., Menet J., Sugino K., Horwich M.D., Weissbein U., Nawathean P., Vagin V., Zamore P., Nelson S. and Rosbash M. “A role for miRNAs in the Drosophila circadian clock”. Genes Dev. 23(8):2179 (2009).
- Featured in Nature Rev. Neurosciences (Oct 2009).
- Kadener S., Rodriguez J., Abruzzi K. and Rosbash M. “Genome-wide identification of targets of the drosha-pasha/DGCR8 complex”. RNA 15(4): 537 (2009).
- Kadener S., Schoer R., Menet J. and Rosbash M. “Circadian transcription contributes to core period determination in Drosophila”.PLOS Biology 6(5): 119 (2008).
Selected for Faculty of 1000 (Factor 3 Recommended)
- Kadener S., Stoleru D., McDonald M., Nawathean P. and Rosbash M. “Clockwork Orange is a transcriptional repressor and a new Drosophila circadian pacemaker component”. Genes Dev. 21:1675 (2007).
- Rosbash M., Bradley S., Kadener S., Li Y., Luo W., Menet J.S., Nagoshi E., Palm K., Schoer R., Shang Y. and Tang C.H. “Transcriptional feedback and definition of the circadian pacemaker in Drosophila and animals”. Cold Spring Harb Symp Quant Biol.72:75 (2007).
- Kadener S., Villella A., Kula E., Palm K., Pyza E., Botas J., Hall J.C. and Rosbash M. “Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in Drosophila”. Proc Natl Acad Sci U S A. 103:13547 (2006).
Selected for Faculty of 1000 (Factor 6 Must Read).
- Lacadie S.A., Tardiff D.F., Kadener S. and Rosbash M. “In vivo commitment to yeast cotranscriptional splicing is sensitive to transcription elongation mutants”. Genes Dev. 20:2055 (2006).
- Selected for Faculty of 1000 (Factor 3 Recommended).
- Fededa J.P., Petrillo E., Gelfand M.S., Neverov A.D., Kadener S., Nogues G., Pelisch F., Baralle F.E., Muro A.F. and Kornblihtt A.R. “A polar mechanism coordinates different regions of alternative splicing within a single gene”. Mol Cell. 19:393 (2005).
- Brown S.A., Ripperger J., Kadener S., Fleury-Olela F., Vilbois F., Rosbash M. and Schibler U. “PERIOD1-associated proteins modulate the negative limb of the mammalian circadian oscillator”. Science 308:693 (2005).
- de la Mata M., Alonso C.R., Kadener S., Fededa J.P., Blaustein M., Pelisch F., Cramer P., Bentley D. and Kornblihtt A.R. “A slow RNA polymerase II affects alternative splicing in vivo”. Mol Cell 12:525 (2005).
- Selected for Faculty of 1000 (Factor 9 Exceptional).
- Allada R., Kadener S., Nandakumar N. and Rosbash M. “A recessive mutant of Drosophila Clock reveals a role in circadian rhythm amplitude”. EMBO J. 22:3367 (2003).
- Portal D., Espinosa J.M., Lobo G.S., Kadener S., Pereira C.A., de la Mata M., Tang Z., Lin R.J., Kornblihtt A.R., Baralle F.E., Flawia M.M. and Torres H.N. “An early ancestor in the evolution of splicing: a Trypanosoma cruzi serine-arginine-rich protein (TcSR) is functional in cis-splicing”. Mol Biochem Parasitology 127:37 (2003).
- Nogues G., Kadener S., Cramer P., de la Mata M., Fededa J.P., Blaustein M., Srebrow A. and Kornblihtt A.R. “Control of alternative pre-mRNA splicing by RNA Pol II elongation: faster is not always better”. IUBMB Life 55:235 (2003).
- Portal D., Lobo G.S., Kadener S., Prasad J., Espinosa J.M., Pereira C.A., Tang Z., Lin R.J., Manley J.L., Kornblihtt A.R., Flawia M.M. and Torres H.N. “Trypanosoma cruzi TcSRPK, the first protozoan member of the SRPK family, is biochemically and functionally conserved with metazoan SR protein-specific kinases”. Mol Biochem Parasitology 127:9 (2003).
- Nogues G., Kadener S., Cramer P., Bentley D. and Kornblihtt A.R. “Transcriptional activators differ in their abilities to control alternative splicing”. J. Biol Chem 277:43110 (2002).
- Kadener S., Fededa J.P., Rosbash M. and Kornblihtt A.R. “Regulation of alternative splicing by a transcriptional enhancer through RNA pol II elongation”. Proc.Natl Acad Sci USA. 99:8185 (2002). Track II.
- Selected for Faculty of 1000 (Factor 3.0 Recommended).
- Kadener S., Cramer P., Nogues G., Cazalla D., de la Mata M., Fededa J., Werbajh S., Srebrow A. and Kornblihtt A. “Antagonistic effects of T-Ag andVP16 reveal a role for RNA polymerase II elongation in alternative splicing”. EMBO J. 20:5759 (2002).
- Cramer P., Srebrow A., Kadener S., Werbajh S., de la Mata M., Melen G., Nogues G. and Kornblihtt AR. “Coordination between transcription and pre-mRNA processing”. FEBS Lett. 498:179 (2001).
- Cramer P., Cáceres J.F., Cazalla D., Kadener S., Muro, A., Baralle F. and Kornblihtt A. “Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer”. Mol. Cell 4:251 (2001).