Weatheritt Lab

Splicing and Evolution: how to create new exons

We identified a exonisation is controlled by a multilayered mechanism that modulates the "window of opportunity" for cryptic exon recognition.

Avgan et al.
Genome Biology (2019)

Expanding our view of transcriptome complexity

We've created a light-weight, lightening fast method for the quantitative profiling of AS from raw RNA-seq reads at the event-level (Whippet.jl). We identify >30% of human genome under complex splicing events and cancer genomes show more highly complex transcriptomes.

Sterne-Weiler, Weatheritt et al.
Molecular Cell (2018)

Splicing and Evolution: how to create new phenotypes

We identified a series of mammalian-specific alternative splicing events that regulate higher order protein assemblies. This mechanism expands the regulatory complexity of mammalian transcriptomes and proteomes.

Gueroussov, Weatheritt et al.
Cell (2017)

Full List of Publications

• By Journal: Cell (2), Nature (2), Science (1), Chemical Reviews (2), Nat Struc Biol (3), Mol Cell (6), PNAS (1), E-life (1), Nature Communication (1), Science Signal (1), TIBS (1), Protein Sci (1), Mol BioSyst (2), Curr Opin Stru (1), NAR (5), Bioinfomatics (1), Front Neuro (1), Hum Brain Mapp (1), Nature Review Genetics (1), Genome Biology (1), Nature Biotechnology (1), Nature Review Drug Discovery (1)
• By year: 2024 (4), 2023 (4), 2022 (5), 2021 (2), 2020 (4), 2019 (2), 2018 (1), 2017 (2), 2016 (3), 2015 (1), 2014 (7), 2013 (4), 2012 (5), < 2012 (3)


- Alternative splicing: regulation, biological significance and evolution
1) Kjer-Hansen P, Phan TG, Weatheritt RJ. Protein isoform-centric therapeutics: expanding targets and increasing specificity. Nat Rev Drug Discov. 2024 Oct;23(10):759-779. doi: 10.1038/s41573-024-01025-z 2) Kjer-Hansen P, Weatheritt RJ. The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts. Nature Structural & Molecular Biology (NSMB) 2023 Nov 30. doi: 10.1038/s41594-023-01155-9
3) Sinitcyn P, Richards AL, Weatheritt RJ, Brademan DR, Marx H, Meyer JG, Shishkvoa E, Hebert AS, Westphall MS, Blencowe BJ, Cox J, Coon JJ. Deep Human Proteome Sequencing for Global Detection of Mutations and Alternative Splicing. Nature Biotechnology 2023 Mar 23. doi: 10.1038/s41587-023-01714-x.
4) Skvortsova K, Bertrand S, Voronov D, Ducket PE, Ross SE, Magri MS, Maeso I, Weatheritt RJ, Skarmeta JLG, Arnone MI, Escriva H, Bogdanovic O. Active DNA demethylation of developmental cis-regulatory regions predates vertebrate origins Sci Adv. 2022 Dec 2;8(48):eabn2258
5) Bartonicek N, Rouet R, Warren J, Loetsch C, Santos-Rodriguez G, Walters S, Lin F, Zahra D,Blackburn J, Hammond GM, Reis ALM, Deveson IR, Zammit N, Zeraati M, Grey S, Christ D, Mattick JS, Chtanova T, Brink R, Dinger ME, Weatheritt RJ, Sprent J, King C. The retroelement Lx9 puts a brake on the immune response to virus infection. Nature 2022 Aug;608(7924):757-765.
6) Han H, Best AJ, Braunschweig U, Mikolajewicz N, Li JD, Roth J, Chowdhury F, Mantica F, Nabeel-Shah S, Parada G, Brown KR, O'Hanlon D, Wei J, Yao Y, Zid AA, Comsa LC, Jen M, Wang J, Datti A, Gonatopoulos-Pournatzis T, Weatheritt RJ, Greenblatt JF, Wrana JL, Irimia M, Gingras AC, Moffat J, Blencowe BJ. Systematic exploration of dynamic splicing networks reveals conserved multistage regulators of neurogenesis. Molecular Cell 2022 Aug 18;82(16):2982-2999.e14
7) Wang J, Weatheritt RJ, Voineagu I Alu-minating the Mechanisms Underlying Primate Cortex Evolution. Biol Psychiatry 2022 May 19:S0006-3223(22)01273-2
8) Barutcu AR, Wu M, Braunschweig U, Dyakov BJA, Luo Z, Turner KM, Durbic T, Lin ZY, Weatheritt RJ, Maass PG, Gingras AC, Blencowe BJ. Systematic mapping of nuclear domain-associated transcripts reveals speckles and lamina as hubs of functionally distinct retained introns. Molecular Cell. 2022 Feb 9:S1097-2765(21)01072-8
9) Santos-Rodriguez G, Voineagu I, Weatheritt RJ. Evolutionary dynamics of circular RNAs in primates. eLIFE 2021 Sep 20;10:e69148
10) Ha KCH, Sterne-Weiler T, Morris Q, Weatheritt RJ, Blencowe BJ. Differential contribution of transcriptomic regulatory layers in the definition of neuronal identity. Nature Communications 2021 Jan 12;12(1):335.
11) Farini D, Cesari E, Weatheritt RJ, La Sala G, Naro C, Pagliarini V, Bonvissuto D, Medici V, Guerra M, Di Pietro C, Rizzo FR, Musella A, Carola V, Centonze D, Blencowe BJ, Marazziti D, Sette C. A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum. Cell Reports 2020 Jun 2;31(9):107703
12) Luck K, Kim DK, Lambourne L, Spirohn K,..., Weatheritt RJ and HURI Consortium. Nature. 2020 Apr;580(7803):402-408A reference map of the human binary protein interactome.
13) Rodrigues DC, Mufteev M, Weatheritt RJ, Djuric U, Ha KCH, Ross PJ, Wei W, Piekna A, Sartori MA, Byres L, Mok RSF, Zaslavsky K, Pasceri P, Diamandis P, Morris Q, Blencowe BJ, Ellis J. Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Ubiquitination in Rett Syndrome. Cell Reports. 2020 Mar 24;30(12):4179-4196
14) Gonatopoulos-Pournatzis T, Niibori R, Salter EW, Weatheritt RJ, Tsang B, Farhangmehr S, Liang X, Braunschweig U, Roth J, Zhang S, Henderson T, Sharma E, Quesnel-Vallières M, Permanyer J, Maier S, Georgiou J, Irimia M, Sonenberg N, Forman-Kay JD, Gingras AC, Collingridge GL, Woodin MA, Cordes SP, Blencowe BJ. Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions. Molecular Cell. 2020 Jan 25. pii: S1097-2765(20)30006-X.
15) Avgan N, Wang JI, Fernandez-Chamorro J, Weatheritt RJ. Multilayered control of exon acquisition permits the emergence of novel forms of regulatory control. Genome Biology. 2019 Jul 17;20(1):141
16) Quesnel-Vallières M, Weatheritt RJ, Cordes SP, Blencowe BJ. Autism spectrum disorder: insights into convergent mechanisms from transcriptomics Nat Rev Genetics. 2019 Jan;20(1):51-63
- on cover!
17) Sterne-Weiler T*, Weatheritt RJ*, Best A, Ha KCH, Blencowe BJ. Whippet: an ultra fast and accurate alignment and quantification of RNA-seq data for analysis of alternative splicing. Molecular Cell 2018 Oct 4;72(1):187-200.e6
18) Gueroussov S*, Weatheritt RJ*, Sterne-Weiler T, O’Hanlon D, Lin ZY, Gingras AC, Blencowe BJ§. Mammalian-specific regulation of higher-order hnRNP protein assemblies controls alternative splicing. Cell 2017 Jul 13;170(2):324-339.e23.
- research highlighted by Nature Review Molecular Cell Biology
19) Han H, Braunschweig U, Gonatopoulos-Pournatzis T, Weatheritt RJ, Hirsch CL, Ha KCH, Radovani E, Nabell-Shah S, Sterne-Weiler T, Wang J, O’Hanlon D, Pan Q, Ray D, Vizeacoumar F, Datti A, Magomedova L, Cummins CL, Hughes TR, Greenblatt JF, Wrana JL, Moffat J, Blencowe BJ. Multilayered control of alternative splicing regulatory networks by transcription factors. Molecular Cell. 2017 Feb 2;65(3):539-553.e7.
20) Weatheritt RJ, Sterne-Weiler T, Blencowe BJ. (2016) The ribosome-engaged landscape of alternative splicing. Nat Struct Mol Biol. 2016 Dec;23(12):1117-1123
21) Dominguez D, Tsai YH, Weatheritt R, Wang Y, Blencowe BJ, Wang Z. (2016) An extensive program of periodic alternative splicing linked to cell cycle progression. E-life. 2016 Mar 25;5
22) Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T,Babor M, Quesnel-Vallières M, Tapial J, Raj B, O'Hanlon D, Barrios-Rodiles M, Sternberg MJ, Cordes SP, Roth FP, Wrana JL, Geschwind DH, Blencowe BJ. (2014) A highly conserved program of neuronal microexons is misregulatedin autistic brains. Cell. 159(7):1511-23
- perspective in Cell by Yang and Chen, and in EMBO Journal by Darnell. Research highlighted by Nature Review Neuroscience and Faculty of 1000
23) Reyes A, Anders S, Weatheritt RJ, Gibson T.J, Steinmetz L, Huber W. (2013) Drift and conservation of differential exon usage across tissues in primate species. PNAS. 110(38)
24) Weatheritt RJ, Davey NE, Gibson TJ. (2012) Linear motifs confer functional diversity onto splice variants. Nucleic Acids Res 40, 7123-7131
- recommended reading by Nature Review Genetics
25) Weatheritt RJ and Gibson,TJ. (2012) Linear Motifs: Lost in (Pre)Translation Trends Biochem Sci i 37, 333-341 [Review article]

- Genomic and post-transcriptional regulation
26) Latysheva NS, Oates ME, Maddox L, Flock T, Gough J, Buljan M, Weatheritt RJ, Babu MM. (2016) Molecular Principles of Gene Fusion Mediated Rewiring of Protein Interaction Networks in Cancer. Molecular Cell. 2016 Aug 18;63(4):579-92
27) Weatheritt RJ, Gibson TJ, Babu MM. (2014) Asymmetric mRNA localization contributes to fidelity and sensitivity of spatially localized systems. Nat Struct Mol Biol. 21(9); 833-9
- research highlighted by Faculty of 1000 and by Nature.com
28) Weatheritt RJ, Babu MM. (2013) Evolution. The hidden codes that shape protein evolution. Science 342(6164)

- Intrinsically disordered regions and short linear motifs (SLiMs)
29) Latysheva NS, Flock T, Weatheritt RJ, Chavali S, Babu MM. (2015) How do disordered regions achieve comparable functions to structured domains? Protein Sci. 2015 Jun;24(6):909-22 [Review article]
30) Uyar B, Weatheritt RJ, Dinkel H, Davey NE, Gibson TJ. (2014) Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer? Mol BioSyst; 10(10): 2626-42
31) Van Roey K, Uyar, Weatheritt RJ, Dinkel H, Seiler M, Budd A, Gibson TJ, Davey NE. (2014) Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation. Chemical Reviews. 114(13):6733-78 [Review article]
32) Van der Lee R, Buljan M*, Lang B*, Weatheritt RJ*, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM, Kriwacki RW, Oldfield CJ, Pappu RV, Tompa P, Uversky VN, Wright PE, Babu MM. (2014) Classification of Intrinsically Disordered Regions and Proteins. Chemical Reviews 114 (13): 6589-631 [Review article]
33) Flock T*, Weatheritt RJ*, Latsheva NS, Babu MM§. (2014) Controlling entropy to tune the functions of intrinsically disordered regions. Curr Opin Struct Biol. 2014 Jun;26C:62-7 [Review article]
34) Dinkel H, Van Roey K, Michael S, Davey NE, Weatheritt RJ, Born D, Speck T, Krüger D, Grebnev G, Kuban M, Strumillo M, Uyar B, Budd A, Altenberg B, Seiler M, Chemes LB, Glavina J, Sánchez IE, Diella F, Gibson TJ. (2014) The eukaryotic linear motif resource ELM: 10 years and counting. Nucleic Acids Res D259-66
35) Van Roey K, Dinkel H*, Weatheritt, RJ*, Gibson TJ, Davey NE. (2013) The switches.ELM resource: a compendium of conditional regulatory interfaces within the intrinsically disordered proteome. Science Signaling. 6(269): rs7
36) Weatheritt RJ, Jehl P, Dinkel H, Gibson TJ. (2012) iELM – a web server to explore short linear motif mediated interactions Nucleic Acids Res. doi: 40, W364-9
37) Weatheritt RJ, Luck K, Petsalaki E, Davey NE, Gibson TJ. (2012) The identification of short linear motif mediated interfaces within the human interactome Bioinformatics 28(7):976-982
38) Davey NE, Van Roey K*, Weatheritt RJ*, Toedt G, Uyar B, Altenberg B, Budd A, Diella F, Dinkel H, Gibson TJ. (2012) Attributes of short linear motifs. Mol Biosyst 8, 268-281.
39) Dinkel H, Michael S, Weatheritt RJ, Davey NE, Van Roey K, Altenberg B, Toedt G, Uyar B, Seiler M, Budd A, Jodicke L, Dammert MA, Schroeter C, Hammer M, Schmidt T, Jehl P, McGuigan C, Dymecka M, Chica C, Luck K, Via A, Chatr-Aryamontri A, Haslam N, Grebnev G, Edwards RJ, Steinmetz MO, Meiselbach H, Diella F, Gibson TJ. (2012) ELM--the database of eukaryotic linear motifs. Nucleic Acids Res 40, D242-D251.
40) Gould CM, Diella F, Via A, Puntervoll P, Gemund C, Chabanis-Davidson S, Michael S, Sayadi A, Bryne JC, Chica C, Seiler M, Davey NE, Haslam N, Weatheritt RJ, Budd A, Hughes T, Pas J, Rychlewski L, Trave G, Aasland R, Helmer-Citterich M, Linding R, Gibson TJ. (2010) ELM: the status of the 2010 eukaryotic linear motif resource. Nucleic Acids Res 38, D167-80.

- Neuroscience
41) Yanashima R, Kitagawa N, Matsubara Y, Weatheritt R, Oka K, Kikuchi S, Tomita M, Ishizaki S. (2009) Network Features and Pathway Analyses of a Signal Transduction Cascade. Front Neuroinform 3, 13.
42) Krumbholz K, Nobis EA, Weatheritt RJ, Fink GR. (2009) Executive control of spatial attention shifts in the auditory compared to the visual modality. Hum Brain Mapp 30, 1457-146