Andrea grew up in Procida, a little island in the bay of Naples, Italy. He studied Molecular Biology at the University of Naples Federico II and worked at the Italian National Cancer Institute for his thesis. He received his MSc degree in Molecular Biology (summa cum laude) in 2002. Subsequently, he joined Prof. Maurizio D’Esposito’s group at Institute of Genetics and Biophysics (IGB-National Council of Research, CNR), Naples, studying the role of chromatin and DNA modifications in cancer - and this was the time when his interest in epigenetics began. He decided to stay in D’Esposito’s lab to do his PhD, focusing on the epigenetic mechanism of SPRY3 gene silencing in humans.
As a part of his Doctoral training, Andrea came to Prof. Neil Brockdorff’s lab at the Imperial College London in 2006 as a visiting graduate student. Here he became interested in X inactivation and decided to choose this topic for his postdoc. After having his viva and receiving his PhD degree, Andrea joined the Brockdorff lab at the University of Oxford. Andrea studied the epigenetics of X chromosome inactivation, focusing on understanding how Xist mediates gene silencing. In particular, he was interested in the interplay between Xist and Polycomb Repressive Complexes. He proved that Xist and PRC2 do not interact directly, moving the balance of the much-debated Xist-mediated PRC2 recruitment model toward an indirect recruitment one. Building on this, he set up a genome-wide RNAi screen to identify novel factors involved in X chromosome inactivation and run a set of screens. Based on his pioneering system, the lab has identified important regulators of X inactivation. At the end of 2013, Andrea decided to move on with his career and returned to Italy. Back home, Andrea joined Prof. Phil Avner’s group at the EMBL-Rome as an EMBL-fellow to study the initiation phase of mouse X inactivation, particularly the role of chromatin remodelers in Xist and Tsix regulation.
In 2018 Andrea started his-own laboratory at the Blizard Institute, Queen Mary University of London. His primary research focuses are epigenetics, X chromosome inactivation and lncRNAs. The Cerase Lab is currently working in X Chromosome inactivation (XCI) and XCI reversal using cell and animal models. The lab is also interested in X-linked neurodevelopmental disorders such as Rett and CDKL5 syndromes. The long-term lab plan is to study the epigenetic basis of brain development in health and disease with a particular focus on the role of lncRNAs and chromatin architecture.
He is actively involved in science divulgation since his time at the University of Oxford and he regularly writes for several magazines. He is acting as an editor for many journals and as a referee for Italian, UK and international body of funding and several journals. He is an associate fellow of the Higher Education Academy (AFHEA).
PBLs in Human Development, Cardiorespiratory system and Neurobiology I and II.
PhD positions potentially available.
The lab research interests are in epigenetics, gene expression and nuclear organization. These include X chromosome Inactivation and reactivation, spatial control of gene expression and long non-coding RNAs at single gene and genome-wide level.
Line of research #1
XCI reversal, a small molecule screening
The human X-chromosome carries ~20-30% of genes associated to intellectual disabilities. Mutations of genes on the X-chromosome account for up to 20% of Autism Spectrum Disorders (ASDs). Epimutations on the X-chromosome have also been associated with a number of mental health conditions (i.e. depression, bipolar disorder, schizophrenia) and neurodegeneration. Female mammals silence one of the two X chromosomes to achieve dosage compensation to males through random X chromosome inactivation. As a consequence of this process, females carrying an X-linked mutation, silence either the mutated and the wild-type (WT) copy of the gene, generally in a 50-50 ratio. Therefore, females have a natural “reservoir” of non-mutated dormant genes that can be reactivated. It is possible to reactivate “dormant” X-linked genes by drug-treatment that “deactivate” the master regulator of X inactivation, the long non-coding RNA (lncRNA) Xist.
Reactivation of the dormant genes can normalize protein levels and result in functional phenotype rescue. In order to identify small molecules that can specifically block Xist RNA interaction with silencing partners or other Xist-specific functions. We are currently screening for compounds that reactivate the silent wild-type copy of MeCP2 and Cdkl5. Mutations of these genes are causative of Rett and CDKL5 syndromes, respectively, which are very debilitating ASD/intellectual-retardation diseases. Crucially, the diseases associated with mutations in these genes do not lead to neurodegeneration, which makes them curable in the post-natal/adult state, as shown by previous research.
Line of research #2
Discovery and characterization of novel classes of brain-specific lncRNAs
Work in cell lines and mouse models supports the hypothesis that lncRNAs are important mediators of cellular functions regulating different levels of gene expression. LncRNAs have been shown to work on four regulatory levels: i) as macromolecular scaffolding for protein recruitment; ii) as molecular sponges for sequestering regulatory ncRNAs, mRNA or proteins; iii) as a genomic 3D organizer; iv) as cis/trans-regulatory elements regulating transcription and RNA-splicing. A noticeable example of a multitasking lncRNA is Xist, the master regulator of X chromosome Inactivation (XCI). lncRNAs are fundamental regulators of gene expression. We believe that it is possible to hypothesize the existence of “master” lncRNAs regulating hundreds of genes during brain development.
The objective of this research is finding novel candidate lncRNAs that potentially regulate the expression of protein-coding genes controlling brain development and function. Of pivotal interest will be the analysis of lncRNAs associated with disease during brain development and as a function of environmental clues such as stress diet, chemicals, and aging.
Line of research #3
Role of lncRNAs in phase separation, aggregation and in neurodegenerative disorders
Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 bases that lack coding potential. RNA contributes to the formation of membrane-less organelles such as paraspeckles and stress granules. Xist, the master regulator of X chromosome inactivation (XCI), induces large-scale heterochromatinization of the entire X-chromosome accumulating in large granule-like assemblies. We recently suggested that Xist stabilises XCI by recruiting RNA-binding proteins by a mechanism of liquid-liquid phase separation (Cerase et al, 2019). Xist RNA has six conserved repetitive regions, named A to F, reported to be essential for its function. These regions sustain most of the interactions with proteins (Pintacuda et al, 2017). In particular these regions interact with intrinsically disordered proteins, which are essential for phase separation (Cerase et al, 2019). We aim to create inducible KD lines of Xist-interacting proteins in mouse embryonic stem cells (mESCs) in order to establish which molecules are needed per cell to form a granule. We also aim to create inducible Xist deletions to establish what regions of Xist are needed for the process by means of CRISPR/Cas9 technology. We aim to use all this data to simulate granule formation in wild type (WT) and perturbed cells. We will generate simple yet general mathematical models that can be applied to RNA-driven phase separation. This can have broad applicability and relevance in pathologies such as neurodegeneration, especially in the context of anti-aggregation drug development.
Nerea Blanes (Lab technician)
Giuseppe Trigiante (Postdoc)
Justyna Skonieczna (Intern)
Adrianna Dabrowska (Student)
Cyntia Voke Lundgren (Student)
Alexander N. Young (Lab technician)
Lorena Galiano (Lab technician)
Cerase A.*,π, Armaos A.*, Neumayer C., Avner P., Guttmanπ, and Tartaglia G.π. Phase separation drives X chromosome Inactivation: a hypothesis. πCorrespondent author. Nat. Str. Mol. Bio. 2019 May; 26(5):331-334
Cirillo D., Blanco M., Armaos A., Buness A., Avner P., Gutmann M., Cerase A* and Tartaglia G.*, Quantitative predictions of protein interactions with long non-coding RNA. Nature Methods, 2016 Dec 29;14(1):5-6 *Correspondent author
Chen C.K., Blanco M., Jackson C., Aznauryan E., Ollikainen N., Surka C., Chow A., Cerase A., McDonel P., Guttman M. Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science, 2016 Oct 28;354(6311):468-472
Moindrot B.*, Cerase A.*, Coker H., Masui O., Grizenhout A., Pintacuda G., Schermelleh L., Nesterova T.B., Pintacuta G., Brockdorff N. A pooled shRNA screen identifies Rbm15, Spen and Wtap as factors required for Xist RNA-mediated silencing. Cell Reports, 2015 Jul 28. *First author
Cerase A., Smeets D., Tang Y.A., Gdula M., Kraus F. Spivakov M., Moindrot B., Leleu M., Tattermusch A., Demmerle J., Nesterova T.B., Green C., Otte A.P., Schermelleh L. and Brockdorff N. Spatial separation of Xist-RNA and Polycomb proteins revealed by super resolution microscopy. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2235-40
The lab is actively engaged in outreach and divulgation activities in the context of Autism and relates new therapies.