Oncotarget

Research Papers:

Barrier-to-Autointegration Factor (BAF) involvement in prelamin A-related chromatin organization changes

Manuela Loi, Vittoria Cenni, Serena Duchi, Stefano Squarzoni, Carlos Lopez- Otin, Roland Foisner, Giovanna Lattanzi and Cristina Capanni _

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Oncotarget. 2016; 7:15662-15677. https://doi.org/10.18632/oncotarget.6697

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Abstract

Manuela Loi1,2, Vittoria Cenni1,2, Serena Duchi3,4, Stefano Squarzoni1,2, Carlos Lopez-Otin5, Roland Foisner6, Giovanna Lattanzi1,2, Cristina Capanni1,2

1CNR-National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40136 Bologna, Italy

2Laboratory of Musculoskeletal Cell Biology, IOR, 40136 Bologna, Italy

3Osteoarticolar Regeneration Laboratory, Rizzoli Orthopaedic Institute, 40136 Bologna, Italy

4Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40123 Bologna, Italy

5Department of Biochemistry and Molecular Biology, Medical Faculty, Oviedo University, 33006 Oviedo, Spain

6Max F. Perutz Laboratories, Medical University of Vienna, A-1030 Vienna, Austria

Correspondence to:

Cristina Capanni, e-mail: ccapanni@area.bo.cnr.it

Keywords: prelamin A, barrier-to-autointegration factor, chromatin, Hutchinson-Gilford progeria syndrome, Nestor-Guillermo progeria

Received: August 25, 2015     Accepted: November 21, 2015     Published: December 20, 2015

ABSTRACT

Chromatin disorganization is one of the major alterations linked to prelamin A processing impairment. In this study we demonstrate that BAF is necessary to modulate prelamin A effects on chromatin structure. We show that when prelamin A and BAF cannot properly interact no prelamin A-dependent effects on chromatin occur; similar to what is observed in human Nestor Guillermo Progeria Syndrome cells harboring a BAF mutation, in HEK293 cells expressing a BAF mutant unable to bind prelamin A, or in siRNA mediated BAF-depleted HEK293 cells expressing prelamin A. BAF is necessary to induce histone trimethyl-H3K9 as well as HP1-alpha and LAP2-alpha nuclear relocalization in response to prelamin A accumulation. These findings are enforced by electron microscopy evaluations showing how the prelamin A-BAF interaction governs overall chromatin organization. Finally, we demonstrate that the LAP2-alpha nuclear localization defect observed in HGPS cells involves the progerin-BAF interaction, thus establishing a functional link between BAF and prelamin A pathological forms.


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