Journal
ONCOTARGET
Volume 7, Issue 13, Pages 15662-15677Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6697
Keywords
prelamin A; barrier-to-autointegration factor; chromatin; Hutchinson-Gilford progeria syndrome; Nestor-Guillermo progeria
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Funding
- Italian MIUR FIRB [RBAP10KCNS]
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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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