Vicente Pelechano Group
One of the biggest challenges in biology is to understand how apparently identical cells respond differently to the same stimulus. In some cases this differential behaviour can be explained by alterations of their genetic material, however in other cases identical (clonal) cells can also display phenotypically heterogeneous responses. We use state of the art genomic technologies to study the regulatory mechanism leading to the appearance of divergent gene expression programs in clonal population
Transcriptional basis of non-genetic cellular heterogeneity
In the last few years, the biomedical field has suffered a revolution thanks to the development of the massive parallel sequencing technologies. Now we can obtain the complete genetic information of a person and analyse how this information is being used in a few days and with a limited cost. These technologies make possible a kind of research that was unthinkable a few years back. In the past we have developed a diversity of novel genome-wide approaches to study eukaryotic gene expression using both budding yeast and mammalian cells. By simultaneously sequencing both the 5’ and 3’ ends of each RNA molecule (TIF-Seq), we showed that the complexity of overlapping transcript isoforms had been greatly underestimated. More recently, we have shown how the existence of widespread co-translational mRNA degradation allows to study ribosome dynamics by sequencing mRNA degradation intermediates (5P-Seq). In addition, we have also developed new approaches for the study of other relevant biological questions, such as chromatin structure, single-cell transcriptomics, RNA polymerase elongation or isoform-specific interactions with RNA binding proteins.
Our group, combining experimental and computational work, aims to develop and apply novel genome-wide techniques to address fundamental biological questions with medical implications. We are especially interested in how subtle variations in gene expression can lead to differential cellular phenotypes and investigate:
- How single-cell variability, cellular plasticity and transcriptional memory contribute to the appearance of drug-tolerant cancer persister cells (i.e. those cells that, although genetically sensitive to a drug, do not respond to it).
- The molecular crosstalk between mRNA degradation and ribosome dynamics, and how this process can inform use about cellular phenotypes.
- Develop novel technologies for molecular diagnosis and clinical genomics.
To deliver an integrated view of those process, as well as to refine our knowledge of the basic process of gene expression, we study bacteria, budding yeast and human cell lines at three levels of the gene expression process: epigenetic status, transcript isoform usage and post-transcriptional mRNA regulation
Rapid Detection of COVID-19 Coronavirus Using a Reverse Transcriptional Loop-Mediated Isothermal Amplification (RT-LAMP) Diagnostic Platform.
Yu L, Wu S, Hao X, Dong X, Mao L, Pelechano V, et al
Clin. Chem. 2020 07;66(7):975-977
Chromatin-sensitive cryptic promoters putatively drive expression of alternative protein isoforms in yeast.
Wei W, Hennig BP, Wang J, Zhang Y, Piazza I, Pareja Sanchez Y, et al
Genome Res. 2019 12;29(12):1974-1984
System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection.
Garcia-Moreno M, Noerenberg M, Ni S, Järvelin AI, González-Almela E, Lenz CE, et al
Mol. Cell 2019 04;74(1):196-211.e11
Transcription-driven chromatin repression of Intragenic transcription start sites.
Nielsen M, Ard R, Leng X, Ivanov M, Kindgren P, Pelechano V, et al
PLoS Genet. 2019 02;15(2):e1007969
Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus.
Gaviraghi M, Vivori C, Pareja Sanchez Y, Invernizzi F, Cattaneo A, Santoliquido BM, et al
EMBO J. 2018 12;37(23):
The Lsm1-7/Pat1 complex binds to stress-activated mRNAs and modulates the response to hyperosmotic shock.
Garre E, Pelechano V, Sánchez Del Pino M, Alepuz P, Sunnerhagen P
PLoS Genet. 2018 07;14(7):e1007563
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
Ladds MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, Popova G, et al
Nat Commun 2018 03;9(1):1107
Multiplexed ChIP-Seq Using Direct Nucleosome Barcoding: A Tool for High-Throughput Chromatin Analysis.
Chabbert CD, Adjalley SH, Steinmetz LM, Pelechano V
Methods Mol. Biol. 2018 ;1689():177-194
From transcriptional complexity to cellular phenotypes: Lessons from yeast.
Yeast 2017 12;34(12):475-482
The ribosome assembly gene network is controlled by the feedback regulation of transcription elongation.
Gómez-Herreros F, Margaritis T, Rodríguez-Galán O, Pelechano V, Begley V, Millán-Zambrano G, et al
Nucleic Acids Res. 2017 Sep;45(16):9302-9318
eIF5A facilitates translation termination globally and promotes the elongation of many non polyproline-specific tripeptide sequences.
Pelechano V, Alepuz P
Nucleic Acids Res. 2017 Jul;45(12):7326-7338
A global genetic interaction network maps a wiring diagram of cellular function
M. Costanzo, B. VanderSluis, E. N. Koch, A. Baryshnikova, C. Pons, G. Tan, W. Wang, M. Usaj, J. Hanchard, S. D. Lee, V. Pelechano, E. B. et al
Science, 2016; 353 (6306): aaf1420 DOI: 10.1126/science.aaf1420
Functional interplay between MSL1 and CDK7 controls RNA polymerase II Ser5 phosphorylation.
Chlamydas S, Holz H, Samata M, Chelmicki T, Georgiev P, Pelechano V, et al
Nat. Struct. Mol. Biol. 2016 06;23(6):580-9
Widespread Co-translational RNA Decay Reveals Ribosome Dynamics.
Pelechano V, Wei W, Steinmetz LM
Cell 2015 Jun;161(6):1400-12
Single-cell polyadenylation site mapping reveals 3' isoform choice variability.
Velten L, Anders S, Pekowska A, Järvelin AI, Huber W, Pelechano V, et al
Mol. Syst. Biol. 2015 Jun;11(6):812
A high-throughput ChIP-Seq for large-scale chromatin studies.
Chabbert CD, Adjalley SH, Klaus B, Fritsch ES, Gupta I, Pelechano V, et al
Mol. Syst. Biol. 2015 Jan;11(1):777
Chromatin-dependent regulation of RNA polymerases II and III activity throughout the transcription cycle.
Jordán-Pla A, Gupta I, de Miguel-Jiménez L, Steinmetz LM, Chávez S, Pelechano V, et al
Nucleic Acids Res. 2015 Jan;43(2):787-802
Genome-wide identification of transcript start and end sites by transcript isoform sequencing.
Pelechano V, Wei W, Jakob P, Steinmetz LM
Nat Protoc 2014 Jul;9(7):1740-59
Alternative polyadenylation diversifies post-transcriptional regulation by selective RNA-protein interactions.
Gupta I, Clauder-Münster S, Klaus B, Järvelin AI, Aiyar RS, Benes V, et al
Mol. Syst. Biol. 2014 ;10():719
Extensive transcriptional heterogeneity revealed by isoform profiling.
Pelechano V, Wei W, Steinmetz LM
Nature 2013 May;497(7447):127-31