Pre‐Lamin A processing is linked to heterochromatin organization

Lattanzi, Giovanna; Columbaro, Marta; Mattioli, Elisabetta; Cenni, Vittoria; Camozzi, Daria; Wehnert, Manfred; Santi, Spartaco; Riccio, Massimo; Coco, Rosalba Del; Maraldi, Nadir M.; Squarzoni, Stefano; Foisner, Roland; Capanni, Cristina

doi:10.1002/jcb.21467

Cited by 69 publications

(98 citation statements)

References 39 publications

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“…In particular, we studied BAF localization and expression in HEK293 cells transfected with either FLAG-tagged lamin A (LA-WT, wild-type lamin A), non-farnesylated prelamin A (LA-C661M) and carboxymethylated farnesylated prelamin A, which cannot be processed to mature lamin A (LA-L647R). 9,11 In accordance with previously reported results, BAF immunofluorescence staining performed in untransfected cells showed that this DNA-binding protein is localized heterogeneously between the nucleus and cytoplasm 18 ( Fig. 1A, asterisk).…”

Section: Resultssupporting

confidence: 92%

“…1A, arrows). [9][10][11] Interestingly in HEK293 cells, LA-C661M aggregates could be also detected at the nuclear periphery. BAF nuclear levels increased in cells accumulating non-farnesylated prelamin A.…”

Section: Resultsmentioning

confidence: 91%

“…In this regard, we have demonstrated that the accumulation of different intermediates of lamin A processing are able to affect chromatin organization. 9,10 Thus, when unprocessable prelamin A increases in the nucleus, heterochromatin intranuclear foci are observed. In contrast, when uncleavable farnesylated prelamin A accumulates, heterochromatin loss is observed.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, when uncleavable farnesylated prelamin A accumulates, heterochromatin loss is observed. 9,10 Recently, the ability of prelamin A to modify chromatin organization has been considered to have a physiological role. In particular we observed that the prelamin A maturation pathway seems to be differently modulated during muscle differentiation, 11 a physiological event characterized by a large reorganization of chromatin.…”

Section: Introductionmentioning

confidence: 99%

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Lamin A precursor induces barrier-to-autointegration factor nuclear localization

Capanni¹,

Cenni²,

Haraguchi

et al. 2010

Cell Cycle

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Lamin A, a protein component of the nuclear lamina, is synthesized as a precursor named prelamin A, whose multi-step maturation process involves different protein intermediates. As demonstrated in laminopathies such as familial partial lipodystrophy, mandibuloacral dysplasia, Werner syndrome, Hutchinson-Gilford progeria syndrome and restrictive dermopathy, failure of prelamin A processing results in the accumulation of lamin A protein precursors inside the nucleus which dominantly produces aberrant chromatin structure. To understand if nuclear lamina components may be involved in prelamin A chromatin remodeling effects, we investigated barrier-to-autointegration factor (BAF) localization and expression in prelamin A accumulating cells. BAF is a DNA-binding protein that interacts directly with histones, lamins and LEM-domain proteins and has roles in chromatin structure, mitosis and gene regulation. In this study, we show that the BAF heterogeneous localization between nucleus and cytoplasm observed in HEK293 cycling cells changes in response to prelamin A accumulation. In particular, we observed that the accumulation of lamin A, non-farnesylated prelamin A and farnesylated carboxymethylated lamin A precursors induce BAF nuclear translocation. Moreover, we show that the treatment of human fibroblasts with prelamin A interfering drugs results in similar changes. Finally, we report that the accumulation of progerin, a truncated form of farnesylated and carboxymethylated prelamin A identified in Hutchinson-Gilford progeria syndrome cells, induces BAF recruitment in the nucleus. These findings are supported by coimmunoprecipitation of prelamin A or progerin with BAF in vivo and suggest that BAF could mediate prelamin A-induced chromatin effects

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lamin A precursor induces barrier-to-autointegration factor nuclear localization

Capanni¹,

Cenni²,

Haraguchi

et al. 2010

Cell Cycle

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“…Moreover, lamin A/C has been demonstrated to bind gene promoters or neighboring domains and this binding has been linked to distinct transcriptional outcomes (Lee, Welton, Smith, & Kennedy, 2009; Lund & Collas, 2013; Mattout et al, 2011). Finally, a clear link has been established between stress‐induced chromatin remodeling, including acetylation or methylation of HDAC2 substrates H3 histone lysine 9 (H3K9) and H4 histone lysine 16 (H4K16), and lamin A/C posttranslational modifications (Ghosh et al, 2015; Lattanzi et al, 2007, 2014 ; Liu et al, 2013; Mattioli et al, 2008). Based on the whole evaluation of those reported data, we wondered if HDAC2 could mediate lamin A/C‐dependent effects on p21 expression during DDR.…”

Section: Introductionmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Effects of prelamin A processing inhibitors on the differentiation and activity of human osteoclasts

Zini¹,

Avnet²,

Ghisu

et al. 2008

J of Cellular Biochemistry

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Osteoclast differentiation is a complex process involving cytoskeleton and nuclear reorganization. Osteoclasts regulate bone homeostasis and have a key role in bone degenerative processes. Osteolysis and osteoporosis characterize a subset of laminopathies, inherited disorders due to defects in lamin A/C. Laminopathies featuring bone resorption are characterized, at the molecular level, by anomalous accumulation of the unprocessed lamin A precursor, called prelamin A. To obtain a suitable cell model to study prelamin A effects on osteoclasts, prelamin A processing inhibitors FTI-277 or AFCMe were applied to peripheral blood monocytes induced to differentiate towards the osteoclastic lineage. Previous studies have shown that treatment with FTI-277 causes accumulation of non-farnesylated prelamin A, while AFCMe inhibition of prelamin A maturation causes accumulation of a farnesylated form. We demonstrate that monocytes subjected to FTI-277 treatment and mostly those subjected to AFCMe administration, differentiate towards the osteoclastic lineage more efficiently than untreated monocytes, in terms of number of multinucleated giant cells, mRNA expression of osteoclast-related genes and TRACP 5b activity. On the other hand, the bone resorption activity of osteoclasts obtained in the presence of high prelamin A levels is lower with respect to control osteoclasts. This finding may help the understanding of the osteolytic and osteoporotic processes that characterize progeroid laminopathies.

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Pre‐Lamin A processing is linked to heterochromatin organization

Cited by 69 publications

References 39 publications

Lamin A precursor induces barrier-to-autointegration factor nuclear localization

Lamin A precursor induces barrier-to-autointegration factor nuclear localization

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Effects of prelamin A processing inhibitors on the differentiation and activity of human osteoclasts

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