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Your search keyword '"chromatin remodelling factors"' showing total 6 results
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6 results on '"chromatin remodelling factors"'

1. How does the chromatin remodeler ATRX identify its targets in the genome?

Author

Nguyen, Diu Thi Thanh and Gibbons, Richard

Subjects
616.85, Clinical laboratory sciences, ATR-X syndrome, chromatin remodelling factors, R-loops, G-quadruplexes, GC-rich tandem repeats, non-B DNA structures
Abstract

ATRX is a chromatin remodeling protein associated with X-linked Alpha-Thalassemia Mental Retardation syndrome and cancers that use the Alternative Lengthening of Telomere pathway. In the absence of ATRX there is a DNA damage response associated with telomeres and the expression of certain genes are perturbed. Recent findings (Law et al, 2010 Cell) have shown that ATRX is preferentially enriched at GC-rich tandem repeats in the genome. The mechanism for this localisation is unknown but may be related to the potential for these GC-rich tandem repeats to adopt non-B form DNA structures; ATRX has been shown to bind such structures (G4) in vitro. This study aims to understand the specific factors of the repeats that signal ATRX targeting. To address the research questions, an experimental system was developed, in which known targets, the ψζ VNTR and telomere repeats, were inserted into an inducible ectopic gene in the 293T-Rex cell line by site-directed recombination. ATRX was found to be enriched at the ectopic repeats compared to an endogenous negative control suggesting that it is recruited by the repeats independent of its original context. Furthermore, ATRX enrichment increased upon transcription of the ectopic gene, and this was dependent on the orientation of the repeat with the non-template strand being G-rich. Interestingly, when the repeat was transcribed, the distribution of ATRX across the repeats was asymmetrical with most ATRX binding downstream of the repeat. Moreover, there was a direct correlation between the repeat size and level of ATRX bound: the longer the repeat the higher the increase in ATRX enrichment. To determine the signal for ATRX binding, assays were performed to look for features which reflected the distribution of ATRX including H3K9me3, RNA polII, G4, R loops and DNA supercoiling. R loops look to be a strong candidate for the signaling of ATRX binding.

Published
2014

2. SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type.

Author

Errichiello, Edoardo, Mustafa, Noor, Vetro, Annalisa, Notarangelo, Lucia Dora, de Jonge, Hugo, Rinaldi, Berardo, Vergani, Debora, Giglio, Sabrina Rita, Morbini, Patrizia, and Zuffardi, Orsetta

Abstract

SMARCA4 chromatin remodelling factor is mutated in 11% of Coffin-Siris syndrome (CSS) patients and in almost all small-cell carcinoma of the ovary hypercalcaemic type (SCCOHT) tumours. Missense mutations with gain-of-function or dominant-negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole-exome sequencing to study a 15-year-old patient with mild CSS who concomitantly developed SCCOHT at age 13 years. Interestingly, our patient also showed congenital microphthalmia, which has never previously been reported in CSS patients. We detected a de novo germline heterozygous nonsense mutation in exon 19 of SMARCA4 (c.2935C > T;p.Arg979*), and a somatic frameshift mutation in exon 6 (c.1236_1236delC;p.Gln413Argfs*88), causing complete loss of SMARCA4 immunostaining in the tumour. The immunohistochemical findings are supported by the observation that the c.2935C > T mutant transcript was detected by reverse transcription polymerase chain reaction at a much lower level than the wild-type allele in whole blood and the lymphoblastoid cell line of the proband, confirming nonsense-mediated mRNA decay. Accordingly, immunoblotting demonstrated that there was approximately half the amount of SMARCA4 protein in the proband's cells as in controls. This study suggests that SMARCA4 constitutional mutations associated with CSS are not necessarily non-truncating, and that haploinsufficiency may explain milder CSS phenotypes, as previously reported for haploinsufficient ARID1B. In addition, our case supports the dual role of chromatin remodellers in developmental disorders and cancer, as well as the involvement of SMARCA4 in microphthalmia, confirming previous findings in mouse models and the DECIPHER database. Finally, we speculate that mild CSS might be under-recognized in a proportion of SCCOHT patients harbouring SMARCA4 mutations. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Published
2017
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3. Epigenetic factors and cardiac development.

Author

van Weerd, Jan Hendrick, Koshiba-Takeuchi, Kazuko, Kwon, Chulan, and Takeuchi, Jun K.

Subjects
*HEART development, *HEART abnormalities, *HUMAN abnormalities, *CARDIOLOGY, *TRANSCRIPTION factors, *GENETICS, *DEVELOPMENTAL biology, *CELL differentiation
Abstract

Congenital heart malformations remain the leading cause of death related to birth defects. Recent advances in developmental and regenerative cardiology have shed light on a mechanistic understanding of heart development that is controlled by a transcriptional network of genetic and epigenetic factors. This article reviews the roles of chromatin remodelling factors important for cardiac development with the current knowledge of cardiac morphogenesis, regeneration, and direct cardiac differentiation. In the last 5 years, critical roles of epigenetic factors have been revealed in the cardiac research field. [ABSTRACT FROM AUTHOR]

Published
2011
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5. SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type

Author

Edoardo, Errichiello, Noor, Mustafa, Annalisa, Vetro, Lucia Dora, Notarangelo, Hugo, de Jonge, Berardo, Rinaldi, Debora, Vergani, Sabrina Rita, Giglio, Patrizia, Morbini, and Orsetta, Zuffardi

Subjects
Male, Heterozygote, Adolescent, Blotting, Western, DNA Mutational Analysis, Micrognathism, Coffin–Siris syndrome (CSS), Intellectual Disability, chromatin remodelling factors, Biomarkers, Tumor, Humans, Microphthalmos, nonsense‐mediated mRNA decay (NMD), Abnormalities, Multiple, Genetic Predisposition to Disease, RNA, Messenger, Carcinoma, Small Cell, Frameshift Mutation, SMARCA4/BRG1, Ovarian Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, DNA Helicases, Brief Definitive Report, Nuclear Proteins, Middle Aged, Immunohistochemistry, Pedigree, haploinsufficiency, Phenotype, microphthalmia, Codon, Nonsense, Face, Hypercalcemia, Brief Definitive Reports, Female, small‐cell carcinoma of the ovary hypercalcaemic type (SCCOHT), Hand Deformities, Congenital, Neck, Transcription Factors, SWI/SNF complex, whole‐exome sequencing (WES)
Abstract

SMARCA4 chromatin remodelling factor is mutated in 11% of Coffin–Siris syndrome (CSS) patients and in almost all small‐cell carcinoma of the ovary hypercalcaemic type (SCCOHT) tumours. Missense mutations with gain‐of‐function or dominant‐negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole‐exome sequencing to study a 15‐year‐old patient with mild CSS who concomitantly developed SCCOHT at age 13 years. Interestingly, our patient also showed congenital microphthalmia, which has never previously been reported in CSS patients. We detected a de novo germline heterozygous nonsense mutation in exon 19 of SMARCA4 (c.2935C > T;p.Arg979*), and a somatic frameshift mutation in exon 6 (c.1236_1236delC;p.Gln413Argfs*88), causing complete loss of SMARCA4 immunostaining in the tumour. The immunohistochemical findings are supported by the observation that the c.2935C > T mutant transcript was detected by reverse transcription polymerase chain reaction at a much lower level than the wild‐type allele in whole blood and the lymphoblastoid cell line of the proband, confirming nonsense‐mediated mRNA decay. Accordingly, immunoblotting demonstrated that there was approximately half the amount of SMARCA4 protein in the proband's cells as in controls. This study suggests that SMARCA4 constitutional mutations associated with CSS are not necessarily non‐truncating, and that haploinsufficiency may explain milder CSS phenotypes, as previously reported for haploinsufficient ARID1B. In addition, our case supports the dual role of chromatin remodellers in developmental disorders and cancer, as well as the involvement of SMARCA4 in microphthalmia, confirming previous findings in mouse models and the DECIPHER database. Finally, we speculate that mild CSS might be under‐recognized in a proportion of SCCOHT patients harbouring SMARCA4 mutations. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Published
2017

6. SMARCA4 inactivating mutations cause concomitant Coffin–Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type

Author

Errichiello, Edoardo, Mustafa, Noor, Vetro, Annalisa, Notarangelo, Lucia Dora, de Jonge, Hugo, Rinaldi, Berardo, Vergani, Debora, Giglio, Sabrina Rita, Morbini, Patrizia, and Zuffardi, Orsetta

Subjects
chromatin remodelling factors, Coffin–Siris syndrome (CSS), haploinsufficiency, intellectual disability, microphthalmia, nonsense-mediated mRNA decay (NMD), small-cell carcinoma of the ovary hypercalcaemic type (SCCOHT), SMARCA4/BRG1, SWI/SNF complex, whole-exome sequencing (WES), Abnormalities, Multiple, Adolescent, Biomarkers, Tumor, Blotting, Western, Carcinoma, Small Cell, DNA Helicases, DNA Mutational Analysis, Face, Female, Genetic Predisposition to Disease, Hand Deformities, Congenital, Heterozygote, Humans, Hypercalcemia, Immunohistochemistry, Intellectual Disability, Male, Micrognathism, Microphthalmos, Middle Aged, Neck, Nuclear Proteins, Ovarian Neoplasms, Pedigree, Phenotype, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Codon, Nonsense, Frameshift Mutation, 2734
Published
2017

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