Chromatin and Nuclear Architecture

 

Team

Bianchi Andrea, PhD Student bianchi@ingm.org
Lucini Federica, Predoctoral Fellowlucini@ingm.org
Pegoli Gloria, Undergraduate Student
Valsoni Sara, Post Doc valsoni@ingm.org

Scientific Background

Chiara Lanzuolo obtained degree with honours in Biological Sciences, at University of Naples “Federico II” in 1998, and, in 2002, she obtained her PhD in Genetics at the Ecole Normale Superieure of Lyon, France. From 2002 to 2009, she worked as “postdoctoral research scientist” in Dulbecco Telethon Institute, at the Institute of Genetics and Biophysics (IGB-CNR) Naples, Italy and then at the Institute of Cellular Biology and Neurobiology (IBCN-CNR) Rome, Italy. From 2009 Chiara Lanzuolo holds a three years Researcher position at Institute of Cellular Biology and Neurobiology (IBCN-CNR) Rome, Italy. ln 2011 Dr. Lanzuolo was awarded by MIUR (Italian Ministry of Research and University), with the grant “Futuro in ricerca 2010″ to start her independent research activity.

Projects

Over the past 10 years a large number of mutations in the human lamin genes have been associated with numerous diseases collectively termed laminopathies. Although it is clear that structural organization and epigenetic regulation of chromatin are altered in diseases caused by mutant lamins, nothing is known about the specific functions of lamins in these processes under normal physiological conditions. The Polycomb group (PcG) of proteins is part of a conserved epigenetic cell memory system that prevents changes in cell lineage identity by maintaining transcription patterns through cell divisions via chromatin structure. We hypothesize an involvement of lamin in the coordination of gene expression regulating contemporary sub-set of genes throughout direct or indirect interactions with Polycomb epigenetic complexes.

Our studies are focused on physiological processes such as differentiation and senescence and pathological conditions as premature senescence and lamin disorders to find the role Lamin A in the regulation of gene expression. To this aim we combine molecular and cellular biology, the use of high-resolution techniques, such as Chip, FISH, 4C and time-lapse microscopy supported by high performance computing for the analysis of data.

The ultimate objective will be to produce the fundamental knowledge of functional interactions between Polycomb repressive complexes and Lamin A that could help to untangle the intricate cascade of events at the basis of lamin related diseases, providing new tools for preclinical studies.

In this laboratory, we study epigenetic mechanisms involved in lamin dependent disease with the following projects:

  • Dissecting the role of Lamin A/C in genome organization and regulation
  • Role of LaminA/C-Polycomb crosstalk in Emery Dreifuss Muscular Dystrophy
  • Identification of epigenome alterations in Hutchinson-Gilford Progeria Syndrome

Scientific background

The inner part of the nuclear envelope (NE) is constituted by a complex meshwork of proteins, known as lamins, which confer mechanical support to the nucleus. In vertebrates, lamin proteins have been divided into A and B types. While Lamin B is predominantly present at inner nuclear membrane, Lamin A is also present throughout the nucleoplasm, suggesting a role beyond the maintenance of mechanical stability of the nucleus. Genetic studies confirmed this hypothesis, showing that mice lacking A-type lamins develop abnormalities of cardiac and skeletal muscle and in human mutations of Lamin A/C causes a wide range of diseases, the laminopathies. To date, despite the large number of identified mutations, it is difficult to create a clear correlation between phenotype and genotype. Many different mutations can give rise to the same clinical condition while a single mutation can result in different phenotypes and disease severity, even in the same family. This suggests an involvement of the individual epigenetic background to the disease. Key epigenetic regulators of chromatin architecture are Polycomb group (PcG) of proteins, epigenetic transcriptional repressors that regulate genes primarily involved in differentiation and development. In the nucleus, PcG proteins can be organized as microscopically visible foci termed PcG bodies and high-through-put data together with microscope analysis revealed a specific organization of their targets in chromatin loops. Interestingly, several laminopathies affect physiological processes, such as differentiation and aging, where PcG proteins play a key role. We work on the hypothesis that Lamin A/C and PcG proteins can functionally interact and that alteration of this crosstalk can contribute to disease progression.

Selected publications

Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes
Elisa Cesarini, Chiara Mozzetta, Fabrizia Marullo, Francesco Gregoretti, Annagiusi Gargiulo, Marta Columbaro, Alice Cortesi, Laura Antonelli, Simona Di Pelino, Stefano Squarzoni, Daniela Palacios, Alessio Zippo, Beatrice Bodega, Gennaro Oliva, and Chiara Lanzuolo
J Cell Biol. 2015 Oct 13;6:527. doi: 10.3389/fimmu.2015.00527. eCollection 2015. Review.

PcG mediated higher order chromatin structures modulate replication programs at the Drosophila BX-C
Lo Sardo F*, Lanzuolo C*, Comoglio F, De Bardi M, Paro R, Orlando V
PloS Genetics 2013 Feb 9 * These authors contributed equally

Memories from the Polycomb group of proteins
Lanzuolo C and Orlando V
Annu Rev Genet 2012 Sep 17

Epigenetic alterations in muscular disorders
Lanzuolo C
Comp funct genomics 2012 Jun 18

Concerted epigenetic signatures inheritance at PcG targets through replication
Lanzuolo C
Cell Cycle 2012 Apr 1

PcG complexes set the stage for epigenetic inheritance of gene silencing in early S phase before replication
Lanzuolo C, Lo Sardo F, Diamantini A. Orlando V.
PLoS Genet. 2011 Nov 3

Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex
Lanzuolo C, Lo Sardo F, Diamantini A. Orlando V.
Nat Cell Biol. 2007 Oct 9(10):1167-74

The function of the epigenome in cell reprogramming
Lanzuolo C and Orlando V.
Cell Mol Life Sci, 2007 May 64(9):1043-62

The finger subdomain of yeast telomerase cooperates with Pif1p to limit telomere elongation
Eugster A*, Lanzuolo C*, Bonneton M, Luciano P, Pollice A, Pulitzer JF, Stegberg E, Berthiau AS, Forstemann K, Corda Y, Lingner J, Geli V, Gilson E.
Structl Mol Biol. 2006 Aug 13(8):734-9. * These authors contributed equally

The HTL1 gene (YCR020W-b) of Saccharomyces cerevisiae is necessary for growth at 37°C, and for the conservation of chromosome stability and fertility
Lanzuolo C., Ederle S., Pollice A., Russo F., Storlazzi A. and Pulitzer J.F.
Yeast 2001 Oct 18 (14): 1317-1330

INGM researches are supported by