Methyl CpG–binding proteins induce large-scale chromatin reorganization during terminal differentiation

Brero, Alessandro; Easwaran, Hariharan; Nowak, Danny; Grunewald, Ingrid; Cremer, Thomas; Leonhardt, Heinrich; Cardoso, M. Cristina

doi:10.1083/jcb.200502062

Cited by 208 publications

(282 citation statements)

References 60 publications

(85 reference statements)

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“…For example, the percentage estimate of spots (>1.5 µm diameter) per nucleus in ATRA-treated cells is: +/+, 1%; +/ic, 2%; ic/ic, 32%. Coalescence of centromeric heterochromatin has been previously described in terminally differentiating mouse myotube cells, [51] with evidence presented for central roles in the aggregation process due to increased levels of methylated DNA binding proteins, MeCP2 and MBD2, and of heterochromatic DNA methylation. However, no shift of the centromeric heterochromatin towards the nuclear envelope was reported.…”

Section: Discussionmentioning

confidence: 59%

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Zwerger

Herrmann

Gaines

et al. 2008

Experimental Hematology

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Objective-Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane. Recent studies have demonstrated that genetic deficiency of LBR during granulopoiesis results in hypolobulation of the mature neutrophil nucleus, as observed in human Pelger-Huët anomaly (PHA) and mouse ichthyosis (ic). In this study we have utilized differentiated promyelocytes (EPRO cells) that were derived from the bone marrow of homozygous and heterozygous ichthyosis mice to examine changes to the expression of nuclear envelope proteins and heterochromatin structure that result from deficient LBR expression.Materials and Methods-Wildtype (+/+), heterozygous (+/ic) and homozygous (ic/ic) granulocytic forms of EPRO cells were analyzed for the expression of multiple lamins and inner nuclear envelope proteins by immunostaining and immunoblotting techniques. The heterochromatin architecture was also examined by immunostaining for histone lysine methylation.Results-Wildtype (+/+) and heterozygous (+/ic) granulocytic forms revealed ring-shaped nuclei and contained LBR within the nuclear envelope; ic/ic granulocytes exhibited smaller ovoid nuclei devoid of LBR. The pericentric heterochromatin of undifferentiated and granulocytic ic/ic cells was condensed into larger spots and shifted away from the nuclear envelope, compared to +/+ and +/ic cell forms. Lamin A/C, which is normally not present in mature granulocytes, was significantly elevated in LBR-deficient EPRO cells.Conclusions-Our observations suggest roles for LBR during granulopoiesis which may involve augmenting nuclear membrane growth, facilitating compartmentalization of heterochromatin and promoting down-regulation of lamin A/C expression. Category Granulopoiesis

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Section: Discussionmentioning

confidence: 59%

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Zwerger

Herrmann

Gaines

et al. 2008

Experimental Hematology

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“…In accordance with our previously described results, we observed that 20% of treated cells showed an increase in nuclear size. 12 Western blotting analysis of untreated and treated human fibroblasts showed that BAF protein level did not change after treatment with prelamin A interfering drugs (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

“…GFP-BAF, 17 full-length FLAG-tagged rat prelamin A (LA-WT, pCI mammalian expression vector) and the mutated constructs LA-C661M, LA-L647R and LA-∆50 were transiently transfected into HEK293 cells using FuGene reagent (Roche). 9,12,23,44 Biochemical and immunofluorescence analyses were performed 24 hours after transfection. In human skin fibroblast cells the accumulation of different prelamin A intermediates were obtained using 25 µM mevinolin (Sigma), 10,12 or 20 µM 1-N-acetyl-S-farnesyl-Lcysteine methylester (AFCMe, Alexis).…”

Section: Methodsmentioning

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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“…Among the MBD-containing MBPs, the expression of MBD2 and MeCP2 is very low in proliferating myoblasts but increases during myogenic differentiation [40], suggesting that their main role is in terminal muscle differentiation. In support of this hypothesis, up-regulation of these two proteins leads to the reorganization of heterochromatin, and contributes to the terminal differentiation of myotubes [40]. Upon oxidative stress induction, the nuclear translocation of focal adhesion kinase and its consequent interaction with MBD2 have been reported to induce skeletal muscle differentiation [41].…”

Section: Discussionmentioning

confidence: 99%

The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression

et al. 2011

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Postnatal growth and regeneration of skeletal muscle are carried out mainly by satellite cells, which, upon stimulation, begin to express myogenin (Myog), the critical determinant of myogenic differentiation. DNA methylation status has been associated with the expression of Myog, but the causative mechanism remains almost unknown. Here, we report that the level of CIBZ, a methyl-CpG-binding protein, decreases upon myogenic differentiation of satellitederived C2C12 cells, and during skeletal muscle regeneration in mice. We present data showing that the loss of CIBZ promotes myogenic differentiation, whereas exogenous expression of CIBZ impairs it, in cultured cells. CIBZ binds to a Myog promoter-proximal region and inhibits Myog transcription in a methylation-dependent manner. These data suggest that the suppression of myogenic differentiation by CIBZ is dependent, at least in part, on the regulation of Myog. Our data show that the methylation status of this proximal Myog promoter inversely correlates with Myog transcription in cells and tissues, and during postnatal growth of skeletal muscle. Notably, induction of Myog transcription by CIBZ suppression is independent of the demethylation of CpG sites in the Myog promoter. These observations provide the first reported molecular mechanism illustrating how Myog transcription is coordinately regulated by a methyl-CpG-binding protein and the methylation status of the proximal Myog promoter.

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Methyl CpG–binding proteins induce large-scale chromatin reorganization during terminal differentiation

Cited by 208 publications

References 60 publications

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

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

The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression

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