Diverse lamin-dependent mechanisms interact to control chromatin dynamics

Abstract

Interconnected functional strategies govern chromatin dynamics in eukaryotic cells. In this context, A and B type lamins, the nuclear intermediate filaments, act on diverse platforms involved in tissue homeostasis. On the nuclear side, lamins elicit large scale or fine chromatin conformational changes, affect DNA damage response factors and transcription factor shuttling. On the cytoplasmic side, bridging-molecules, the LINC complex, associate with lamins to coordinate chromatin dynamics with cytoskeleton and extra-cellular signals. Consistent with such a fine tuning, lamin mutations and/or defects in their expression or post-translational processing, as well as mutations in lamin partner genes, cause a heterogeneous group of diseases known as laminopathies. They include muscular dystrophies, cardiomyopathy, lipodystrophies, neuropathies, and progeroid syndromes. The study of chromatin dynamics under pathological conditions, which is summarized in this review, is shedding light on the complex and fascinating role of the nuclear lamina in chromatin regulation.

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

“…Nevertheless, impaired HDAC2 recruitment to the lamin A/C‐containing platform occurs irrespective of the mutated LMNA sequence, a finding that suggests involvement of other molecular defects common to progeroid laminopathies, such as prelamin A accumulation (Cenni et al, 2018). However, the enhanced severity of HGPS cellular phenotype (Camozzi et al, 2014) correlated with the lower level of HDAC2‐lamin A/C interaction in HGPS with respect to other progeroid cells.…”

“…Moreover, proteins involved in repair of stress‐induced DNA damage are recruited by lamins to damaged sites or inside the nuclear compartment (Gibbs‐Seymour, Markiewicz, Bekker‐Jensen, Mailand, & Hutchison, 2015; Gonzalez‐Suarez et al, 2011; Lattanzi et al, 2014). Consistent with these functions, lamin A/C has been implicated in mechanisms related to physiological (Lattanzi et al, 2014) and pathological aging (Evangelisti, Cenni, & Lattanzi, 2016), above all in progeroid laminopathies (Camozzi et al, 2014). Here, we analyzed cells from patients affected by HGPS, a premature aging syndrome linked to LMNA mutations, and observed an altered modulation of CDKN1A , encoding p21, in HGPS under oxidative stress.…”

Proteomic analysis of zoledronic-acid resistant prostate cancer cells unveils novel pathways characterizing an invasive phenotype

“…Indeed, although cancer was confirmed as the IPA-predicted top altered disorder, also connective tissue and hereditary disorders involved a large number of the identified proteins (Table 3). For example loss of function of FLNA has been associated with a wide spectrum of connective tissue and vascular abnormalities [49], glucocorticoid-induced ANXA1 induction has been recently related with immune-mediated inflammation and the pathogenesis of reumathoid artritis [50], laminA recently has been correlated with immune cell functions [51], while both A and B type lamin mutations and/or defects in their expression or post-translational processing, cause a heterogeneous group of diseases known as laminopathies [52]. …”

Phosphorylation of lamins determine their structural properties and signaling functions

“…In light of the study described in the preceeding section, the phosphorylation induced by changes in substrate stiffness will also be consequential for the sequestration, dynamics, mobility, and transport of lamin A. These aspects may, in turn, be consequential for the signaling and transcriptional properties of lamin A. Lamin A interacts with and regulates chromatin organization 38 and lamins also directly and indirectly influence transcription by regulating transcription factors. [39][40][41][42] (Fig.…”