Chromatin remodeling and human disease

Huang, Cheng; Sloan, Emily A.; Boerkoel, Cornelius F.

doi:10.1016/s0959-437x(03)00054-6

Cited by 67 publications

(45 citation statements)

References 49 publications

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“…Therefore, our study provides a link between lamin A mutations and altered chromatin remodeling, supporting a common pathogenetic mechanism. Recent findings suggest that the multisystem nature and the wide spectrum of phenotype variation of several monogenic disorders are attributable to defects of chromatin remodeling (3,7,12,21). Laminopathies represent an excellent model to investigate the molecular basis of this phenomena.…”

Section: Discussionmentioning

confidence: 99%

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Filesi

Gullotta

Lattanzi

et al. 2005

Physiological Genomics

112

132

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by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1␤ and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.LMNA; heterochromatin; heterochromatin protein-1␤; prelamin A MANDIBULOACRAL DYSPLASIA type A [MADA; Online Mendelian Inheritance in Man (OMIM) no. 248370] is a rare and complex disease characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, mottled cutaneous pigmentation, partial lipodystrophy (type A pattern), and insulin resistance (11,17,49). MADA patients seem to be genetically homogeneous, since they show the same mutation (R527H) in the LMNA gene that encodes A-type lamins, lamins A and C (35, 42). In contrast, patients with generalized loss of subcutaneous fat involving the face, trunk, and extremities (type B pattern) carry mutations in the ZMPSTE24 gene (MADB; OMIM no. 608612) (1, 43).Lamins are type V intermediate filament proteins that display a central rod domain, an NH 2 -terminal head domain, and a COOH-terminal globular tail. Lamins A and C, together with B-type lamins, lamin B1 and B2, are the major components of the nuclear lamina, located between the inner nuclear membrane and the chromatin. A growing number of proteins are known to interact with lamins. Numerous experimental evidences suggest that nuclear lamins are involved in many functions including nuclear positioning and shape, chromatin organization, nuclear envelope assembly/disassembly, DNA replication, and regulation of gene transcriptional activity (18).

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Section: Discussionmentioning

confidence: 99%

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Filesi

Gullotta

Lattanzi

et al. 2005

Physiological Genomics

112

132

View full text Add to dashboard Cite

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“…1,2 The nucleosome consists of 147 DNA base pairs wrapped around a core of 8 histones composed of 2 H3/H4 histone dimers flanked by 2 H2A/H2B dimers. Protruding from the histone globular domains are histone tails, which present a rich platform of discrete epitopes subject to chemical modifications, such as acetylation, methylation, and phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

In situ histone landscape of nephrogenesis

et al. 2013

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“…Abnormal alterations to the epigenome have been implicated in a number of human diseases such as cancer, autoimmune syndromes and psychiatric and behavioral disorders (Huang et al, 2003). The plasticity and variety of epigenetic modifications, however, also represent an encouraging array of therapeutic targets that can be altered pharmacologically to reprogram irregular epigenetic profiles.…”

Section: Introductionmentioning

confidence: 99%

5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation

et al. 2006

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The epigenetic silencing of tumor suppressor genes is a common event during carcinogenesis, and often involves aberrant DNA methylation and histone modification of gene regulatory regions, resulting in the formation of a transcriptionally repressive chromatin state. Two examples include the antimetastatic, tumor suppressor genes, desmocollin 3 (DSC3) and MASPIN, which are frequently silenced in this manner in human breast cancer. Treatment of the breast tumor cell lines MDA-MB-231 and UACC 1179 with 5-aza-2 0 -deoxycytidine (5-azaCdR) induced transcriptional reactivation of both genes in a dose-dependent manner. Importantly, DSC3 and MASPIN reactivation was closely and consistently linked with significant decreases in promoter H3 K9 di-methylation. Moreover, 5-aza-CdR treatment also resulted in global decreases in H3 K9 di-methylation, an effect that was linked to its ability to mediate dose-dependent, posttranscriptional decreases in the key enzyme responsible for this epigenetic modification, G9A. Finally, small interfering RNA (siRNA)-mediated knockdown of G9A and DNMT1 led to increased MASPIN expression in MDA-MB-231 cells, to levels that were supra-additive, verifying the importance of these enzymes in maintaining multiple layers of epigenetic repression in breast tumor cells. These results highlight an additional, complimentary mechanism of action for 5-aza-CdR in the reactivation of epigenetically silenced genes, in a manner that is independent of its effects on DNA methylation, further supporting an important role for H3 K9 methylation in the aberrant repression of tumor suppressor genes in human cancer.

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Chromatin remodeling and human disease

Cited by 67 publications

References 49 publications

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

In situ histone landscape of nephrogenesis

5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation

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