The knowledge of epigenetics mechanisms is crucial not only to better understand normal brain development, plasticity and function, but also to dissect chromatin pathways malfunctioning in diseases, thus providing new and powerful tools of intervention through the identification of possible disease modifiers, druggable molecules to be challenged or protected during the early phases of the disease progression. Our laboratory aims to investigate the epigenetic basis of complex brain functions and how alterations in chromatin remodeling complexes, histone modifications patterns and non-coding RNAs might contribute to neurodevelopmental and neurodegenerative disorders, specifically AUTISM and HUNTINGTON’S DISEASE.
CHD8 Haploinsufficiency As A Strong Risk Factor For Autism Spectrum Disorders: Dysregulation In Chromatin Wiring
Loss of function mutations in chromodomain helicase DNA-binding protein 8 (CHD8) represent a strong-effect risk factors for autism spectrum disorder. We previously explored the transcriptional networks that CHD8 regulates in neural progenitor cells by reducing its expression and then integrating transcriptome sequencing with genome-wide CHD8 binding. Now, through a combination of RNA-seq and ChIP-seq genome-wide analyses, we aim to characterize the changes in chromatin status dictated by CHD8 suppression and the effects of these alterations on RNA transcription, morphology, synaptic activity and adhesion properties of terminally differentiated neurons.
SINEUPs, RNA-Based Translational Activators, Of CHD8 Gene As Possible New Avenues Of Therapeutical Intervention For Autism Spectrum Disorder
We recently reported a class of non-coding RNAs (SINEUP) able to augment, in a specific and controlled way, the expression of target proteins. The primary goal of our research is to provide a Proof of Principle of how SINEUPs can increase the translation of CHD8 protein and rescue the phenotypes observed following its suppression in cellular (in vitro) and animal (in vivo, in a chd8-MO knock-down zebrafish) models, thus representing the first approach to therapeutic intervention for haploinsufficiency with high relevance for Autism and many psychiatric disorders.
Genetics and Epigenetics approaches to the study of Huntington’s Disease (HD): transcriptional regulation, alternative splicing alteration and single-cell genomics
This autosomal dominant hereditary neurodegenerative disorder is caused by a CAG trinucleotide repeat expansion in exon 1 of the huntingtin gene which leads to diffuse neuronal loss in the striatum and cortex and eventually to death. Since multiple lines of evidences suggest that altered chromatin modifications, transcriptional deregulation, and alterations in RNA processing (particularly Alternative Splicing) might contribute to the pathological process, we now propose to comprehensively identify how wild-type and mutant huntingtin might regulate the Alternative Splicing outcome by different modes, both direct and indirect, originating the characteristic pleiotropic effects observed during HD progression. We will investigate the potential regulatory role of chromatin structure on alternative splicing process, locally at the HTT gene, and more globally at genome-wide level. We will analyze changes in vivo, in different brain districts of a series of Htt knock-in mouse models, faithfully mimicking the HD mutation, at single-cell level [through laser-capture microdissection and single-cell sequencing] and in HD human post-mortem brain.
Circ-RNAs alteration in Huntington’s Disease pathogenesis
Alternative Splicing regulation is crucial not only to the establishment of a repertoire of protein coding isoforms extremely relevant for normal physiology (particularly relevant in neurons), but also to the biogenesis of circular RNAs (circ-RNAs), a newly re-discovered class of non-coding RNA, unusually stable, produced by the circularization of exons which might affect the abundance of miRNAs, significantly engaged in the functioning of neurons as well as a responsible candidates in neurological disorders. The main goal of our research is to discover early alterations in circ-RNAs locally at the Htt locus, and more globally at genome-wide level. This intriguing hypothesis of huntingtin regulation of Alternative Splicing machinery, thus exerting a larger effect on circRNAs and miRNA regulation, is highly innovative, and crucial to the identification of new, key targets for therapeutic intervention.
- Marta Biagioli, Ph.D., Principal Investigator
- Francesca Di Leva, Ph.D., Molecular Biology, senior postdoctoral fellow
- Emanuela Kerschbamer, Ph.D. Bioinformatics postdoctoral fellow
- Takshashila Tripathi, Ph.D. Molecular Biology, postdoctoral fellow
- Silvia Bassi, Ph. D. Visiting fellow
- Alan Monziani, Bachelor student
- Nithya Arumugam, Master student
We are actively looking for highly motivated, competitive Ph.D. students interested in the challenging and charming topic of “single-cell transcriptomics in Huntington’s Disease”. The project implies highly dynamic international collaborations [Sanger Institute (UK), Harvard Medical School (US)] and training on cutting-edge technologies.
Michael E. Talkowski, Harvard Medical School – Boston
Marcy E. MacDonald, Harvard Medical School – Boston
IhnSik Seong, Harvard Medical School – Boston
Norman Sharpless, University of North Carolina School of Medicine, Chapel Hill
Thierry Vöet, Sanger Institute-EBI Single-Cell Genomics Center, Cambridge (UK)
Stefano Gustincich, S.I.S.S.A. - Trieste and IIT - Genova
Silvia Zucchelli, University of Eastern Piedmont, Novara
Kerschbamer E, and Biagioli M. Huntington’s Disease as Neurodevelopmental Disorder: Altered Chromatin Regulation, Coding, and Non-Coding RNA Transcription. Front. Neurosci.2016 9, 1–5. http://journal.frontiersin.
Marta Biagioli (*), Francesco Ferrari (*), Eric M. Mendenhall, Yijing Zhang, Serkan Erdin, Ravi Vijayvargia, Sonia M. Vallabh, Nicole Solomos, Poornima Manavalan, Ashok Ragavendran, Fatih Ozsolak, Jong Min Lee, Michael E. Talkowski, James F. Gusella, Marcy E. MacDonald, Peter J. Park and Ihn Sik Seong Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation. (*) Joint first authors. Human Molecular Genetics, 2015. http://hmg.oxfordjournals.org/
Pryor WM, Biagioli M, Shahani N, Swarnkar S, Huang WC, Page DT, MacDonald ME, Subramaniam S. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington's disease. Sci Signal. 2014 Oct 28;7(349):ra103.
Sugathan A (*), Biagioli M (*), Golzio C (*), Erdin S (*), Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME. CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4468-77. (*) Joint First authors.
Talkowski ME, Maussion G, Crapper L, Rosenfeld JA, Blumenthal I, Hanscom C, Chiang C, Lindgren A, Pereira S, Ruderfer D, Diallo AB, Lopez JP, Turecki G, Chen ES, Gigek C, Harris DJ, Lip V, An Y, Biagioli M, Macdonald ME, Lin M, Haggarty SJ, Sklar P, Purcell S, Kellis M, Schwartz S, Shaffer LG, Natowicz MR, Shen Y, Morton CC, Gusella JF, Ernst C. Disruption of a large intergenic noncoding RNA in subjects with neurodevelopmental disabilities. Am J Hum Genet. 2012 Dec 7;91(6):1128-34.
Carrieri C (*), Cimatti L (*), Biagioli M, Beugnet A, Zucchelli S, Fedele S, Pesce E, Ferrer I, Collavin L, Santoro C, Forrest AR, Carninci P, Biffo S, Stupka E, Gustincich S. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012 Nov 15;491(7424):454-7. (*) Joint first authors.
Ferrer I, Gómez A, Carmona M, Huesa G, Porta S, Riera-Codina M, Biagioli M, Gustincich S, Aso E. Neuronal hemoglobin is reduced in Alzheimer's disease, argyrophilic grain disease, Parkinson's disease, and dementia with Lewy bodies. J Alzheimers Dis. 2011;23(3):537-50.
Zucchelli S, Codrich M, Marcuzzi F, Pinto M, Vilotti S, Biagioli M, Ferrer I, Gustincich S. TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. Hum Mol Genet. 2010 Oct 1;19(19):3759-70.
Foti R, Zucchelli S, Biagioli M, Roncaglia P, Vilotti S, Calligaris R, Krmac H, Girardini JE, Del Sal G, Gustincich S. Parkinson disease-associated DJ-1 is required for the expression of the glial cell line-derived neurotrophic factor receptor RET in human neuroblastoma cells. J Biol Chem. 2010 Jun 11;285(24):18565-74.
Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P, Simone R, Vlachouli C, Plessy C, Bertin N, Beltrami A, Kobayashi K, Gallo V, Santoro C, Ferrer I, Rivella S, Beltrami CA, Carninci P, Raviola E, Gustincich S. Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15454-9.
Biagioli M, Pifferi S, Ragghianti M, Bucci S, Rizzuto R, Pinton P. Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis. Cell Calcium. 2008 Feb;43(2):184-95.