Campus ICO-Germans Trias i Pujol
Josep Carreras Leukaemia Research Institute
Can Ruti CampusCtra de Can Ruti
Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain
Office 1- 5 (first floor)
Our long-term goal is to understand how gene expression and genome packaging is affected by genetic and epigenetic changes that happen during evolution, development and in disease, in particular cancer. Our research approach is to computationally analyse global datasets in order to understand general mechanisms
We are currently interested in two fundamental questions that we are addressing using a combination of dry and wet-lab experiments. To address these questions, we team up with experts in complementary fields from other research institutes as well as hospitals.
First, we want to understand how epigenetic drug treatments affect gene expression, and chromatin at different contexts in the human genome. Epigenetic drugs currently used in the clinic include those for the treatment of patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome. Our work involves experiments on human cell lines as well as analyses of data from samples extracted from patients undergoing drug treatment. A better understanding of the effects of these drugs and how they work may lead in the future to more personalized treatments.
Second, we want to understand how information about our exposures to different environments may be encoded in molecules - other than DNA – inside germcells that are transmitted from parents to offspring. This trans/inter-generational transmission of epigenetic information can influence an organism’s phenotype, or disease risk. We are interested in understanding what molecules carry such information between generations and the mechanisms involved.
2015 Catalan Predoctoral Fellowship (AGAUR) to Eduard Casas
2015 Group favorably evaluated by the Ramon y Cajal I3 Programme
2014 Spanish National Postdoctoral Fellowship (MINECO) to Yulia Medvedeva
2014 Max Planck - Prince of Asturias Award Mobility Grant to Eduard Casas
2014 Group recognized by the Catalan Research Agency (AGAUR)
2014 EpiGeneSys Travel Fellowship to Eduard Casas
2013 Elected Associate Member of the EU Network of Excellence EpiGeneSys
2011 Spanish National Research Grant (MICINN)
2011 European Reintegration Grant - Framework Programme 7
2010 Ramon y Cajal Award to Tanya Vavouri
Show all publications
Impaired DNA replication derepresses chromatin and generates a transgenerationally inherited epigenetic memory.Sci Adv Aug 2017, 3 (8) e1701143. Epub 16 Aug 2017
Impaired DNA replication is a hallmark of cancer and a cause of genomic instability. We report that, in addition to causing genetic change, impaired DNA replication during embryonic development can have major epigenetic consequences for a genome. In a genome-wide screen, we identified impaired DNA replication as a cause of increased expression from a repressed transgene in Caenorhabditis elegans. The acquired expression state behaved as an "epiallele," being inherited for multiple generations before fully resetting. Derepression was not restricted to the transgene but was caused by a global reduction in heterochromatin-associated histone modifications due to the impaired retention of modified histones on DNA during replication in the early embryo. Impaired DNA replication during development can therefore globally derepress chromatin, creating new intergenerationally inherited epigenetic expression states.More information
Transgenerational transmission of environmental information in C. elegans.Science 21 Apr 2017, 356 (6335) 320-323.
The environment experienced by an animal can sometimes influence gene expression for one or a few subsequent generations. Here, we report the observation that a temperature-induced change in expression from a Caenorhabditis elegans heterochromatic gene array can endure for at least 14 generations. Inheritance is primarily in cis with the locus, occurs through both oocytes and sperm, and is associated with altered trimethylation of histone H3 lysine 9 (H3K9me3) before the onset of zygotic transcription. Expression profiling reveals that temperature-induced expression from endogenous repressed repeats can also be inherited for multiple generations. Long-lasting epigenetic memory of environmental change is therefore possible in this animal.More information
The small RNA content of human sperm reveals pseudogene-derived piRNAs complementary to protein-coding genes.RNA Jun 2015, 21 (6) 1085-95. Epub 22 Apr 2015
At the end of mammalian sperm development, sperm cells expel most of their cytoplasm and dispose of the majority of their RNA. Yet, hundreds of RNA molecules remain in mature sperm. The biological significance of the vast majority of these molecules is unclear. To better understand the processes that generate sperm small RNAs and what roles they may have, we sequenced and characterized the small RNA content of sperm samples from two human fertile individuals. We detected 182 microRNAs, some of which are highly abundant. The most abundant microRNA in sperm is miR-1246 with predicted targets among sperm-specific genes. The most abundant class of small noncoding RNAs in sperm are PIWI-interacting RNAs (piRNAs). Surprisingly, we found that human sperm cells contain piRNAs processed from pseudogenes. Clusters of piRNAs from human testes contain pseudogenes transcribed in the antisense strand and processed into small RNAs. Several human protein-coding genes contain antisense predicted targets of pseudogene-derived piRNAs in the male germline and these piRNAs are still found in mature sperm. Our study provides the most extensive data set and annotation of human sperm small RNAs to date and is a resource for further functional studies on the roles of sperm small RNAs. In addition, we propose that some of the pseudogene-derived human piRNAs may regulate expression of their parent gene in the male germline.More information
Paternal diet defines offspring chromatin state and intergenerational obesity.Cell 4 Dec 2014, 159 (6) 1352-64.
The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution.More information
Sperm epigenomics: challenges and opportunities.Front Genet 2014, 5 330. Epub 18 Sep 2014
Sperm is a highly differentiated cell type whose function is to deliver a haploid genome to the oocyte. The sperm "epigenomes" were traditionally considered to be insignificant - the sperm is transcriptionally inactive, its genome is packaged in sperm-specific protamine toroids instead of nucleosomes, and its DNA methylation profile is erased immediately post-fertilization. Yet, in recent years there has been an increase in the number of reported cases of apparent epigenetic inheritance through the male germline, suggesting that the sperm epigenome may transmit information between generations. At the same time, technical advances have made the genome-wide profiling of different layers of the sperm epigenome feasible. As a result, a large number of datasets have been recently generated and analyzed with the aim to better understand what non-genetic material is contained within the sperm and whether it has any function post-fertilization. Here, we provide an overview of the current knowledge of the sperm epigenomes as well as the challenges in analysing them and the opportunities in understanding the potential non-genetic carriers of information in sperm.More information
PIWI-interacting RNAs - their evolution and their role in epigenetic inheritance and cancer
|Project leader:||Tanya Vavouri|