ATRX binds to atypical chromatin domains at the 3′ exons of zinc finger genes to preserve H3K9me3 enrichment

Valle-García, David; Qadeer, Zulekha A.; McHugh, Domhnall; Ghiraldini, Flávia Gerelli; Chowdhury, Asif H.; Hasson, Dan; Dyer, Michael A.; Recillas‐Targa, Félix; Bernstein, Emily

doi:10.1080/15592294.2016.1169351

Cited by 66 publications

(59 citation statements)

References 76 publications

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“…In the four AA patients with a CNV deletion of ZNF814, the neighbouring gene, ZNF274, was also deleted in one patient. ZNF274 is also a zinc finger protein that acts as a transcriptional factor and complexes with chromatin‐remodeler ATRX (alpha thalassaemia/mental retardation syndrome X‐linked), a SWI/SNF‐family protein . Depletion of ZNF274 results in cell cycle dysfunction, DNA damage and decreased H3K9 trimethylation …”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Petukhova

Patel

Rigo

et al. 2019

Experimental Dermatology

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Alopecia areata (AA) is a highly prevalent autoimmune disease that attacks the hair follicle and leads to hair loss that can range from small patches to complete loss of scalp and body hair. Our previous linkage and genome‐wide association studies (GWAS) generated strong evidence for aetiological contributions from inherited genetic variants at different population frequencies, including both rare mutations and common polymorphisms. Additionally, we conducted gene expression (GE) studies on scalp biopsies of 96 patients and controls to establish signatures of active disease. In this study, we performed an integrative analysis on these two datasets to test the hypothesis that rare CNVs in patients with AA could be leveraged to identify drivers of disease in our AA GE signatures. We analysed copy number variants (CNVs) in a case‐control cohort of 673 patients with AA and 16 311 controls independent of the case‐control cohort of 96 research participants used in our GE study. Using an integrative computational analysis, we identified 14 genes whose expression levels were altered by CNVs in a consistent direction of effect, corresponding to gene expression changes in lesional skin of patients. Four of these genes were affected by CNVs in three or more unrelated patients with AA, including ATG4B and SMARCA2, which are involved in autophagy and chromatin remodelling, respectively. Our findings identified new classes of genes with potential contributions to AA pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Petukhova

Patel

Rigo

et al. 2019

Experimental Dermatology

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“…Fortunately, there is a specific mechanism to prevent this. The heterochromatin-like complexes at the 3′ end of the KRABZNFs act as a focal point for the machinery that incorporates the replacement histone H3.3 into chromatin (Valle-García et al 2016) and in this way the repressive histone modifications are replenished while transcription is ongoing. Specifically, KAP1 binds to DAXX (Elsässer et al 2015), which is a H3.3 specific chaperone that, along with the chromatin remodeller ATRX, is known to target histone H3.3 to periHeterochromatin and 'parent-of-origin' effects centric and telomeric constitutive heterochromatin (Drané et al 2010;Goldberg et al 2010;Wong et al 2010), where H3.3 is tri-methylated on lysine 9 by a SUV39H HMTase (Voon and Wong 2016).…”

Section: Characterization Of Hp1-containing Heterochromatinlike Complmentioning

confidence: 99%

“…Specifically, KAP1 binds to DAXX (Elsässer et al 2015), which is a H3.3 specific chaperone that, along with the chromatin remodeller ATRX, is known to target histone H3.3 to periHeterochromatin and 'parent-of-origin' effects centric and telomeric constitutive heterochromatin (Drané et al 2010;Goldberg et al 2010;Wong et al 2010), where H3.3 is tri-methylated on lysine 9 by a SUV39H HMTase (Voon and Wong 2016). Histone H3.3 is also incorporated at the heterochromatin-like complexes at the 3' end of the KRAB-ZNF genes (Valle-García et al 2016), where it can be tri-methylated at K9H3 by SETDB1 (Frietze et al 2010). Binding of the ATRX-DAAX complex is enhanced by the known interaction of ATRX with both H3K9me3 and HP1, the former through the ADD domain and the latter through an LxVxL motif, and both interfaces are known to combine to localize ATRX to heterochromatin (Eustermann et al 2011).…”

Section: Characterization Of Hp1-containing Heterochromatinlike Complmentioning

confidence: 99%

Heterochromatin and the molecular mechanisms of ‘parent-of-origin’ effects in animals

Singh

2016

J Biosci

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Twenty five years ago it was proposed that conserved components of constitutive heterochromatin assemble heterochromatinlike complexes in euchromatin and this could provide a general mechanism for regulating heritable (cell-to-cell) changes in gene expressibility. As a special case, differences in the assembly of heterochromatin-like complexes on homologous chromosomes might also regulate the parent-of-origin-dependent gene expression observed in placental mammals. Here, the progress made in the intervening period with emphasis on the role of heterochromatin and heterochromatin-like complexes in parent-of-origin effects in animals is reviewed.[Singh PB 2016 Heterochromatin and the molecular mechanisms of 'parent-of-origin' effects in animals. J. Biosci.] http://www.ias.ac.in/jbiosci J. Biosci. * Indian Academy of Sciences DOI: 10.1007/s12038-016-9650-9Keywords. Epigenetics; genomic imprinting; heterochromatin; HP1; KRAB-ZFP Abbreviations used: 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; ADD, ATRX-DNMT3-DNMT3L domain; ATRX, Alpha Thalassemia/Mental Retardation Syndrome X-Linked; CAF-1, chromatin assembly factor 1; CD, chromodomain; CE, controlling element; CF, chromocenter formation; CGIs, CpG islands; CSD, chromo shadow domain; DamID, DNA adenine methyltransferase identification; DAXX, Death Domain associated protein; DNMT1, maintenance DNA methyltransferase 1; DNMT3A, de novo DNA methyltransferase 3A; DNMT3B, de novo DNA methyltransferase 3B; DNMT3L, DNA methyltransferase 3L; ES, embryonic stem; G9a, K9H3 HMTase; GLP, G9a-like protein K9H3 HMTase; gDMRs, germline differentially methylated regions; H3K9me2, di-methylated lysine 9 on histone H3; H3K9me3, tri-methylated lysine 9 on histone H3; H3S10P, phosphorylation of serine 10 on histone H3; H4K20me3, tri-methylated lysine 20 on histone

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“…These genes are expressed in WT ES cells and their expression remained unchanged in mutant ES cells despite loss of KAP1 and H3K9me3 over the 3’ end of these genes. Consistent with this, it has been postulated that 3’ end H3K9me3 recruitment may promote genomic stability and prevent recombination between homologous Zn-finger proteins rather than directly regulate their expression [36,37].…”

Section: Discussionmentioning

confidence: 87%

Epigenetic regulation of unique genes and repetitive elements by the KRAB zinc finger protein ZFP57

Strogantsev

Takahashi

et al. 2019

Preprint

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BackgroundKRAB-zinc finger proteins (KZFPs) represent one of the largest families of DNA binding proteins in vertebrate genomes and appear to have evolved to silence transposable elements (TEs) including endogenous retroviruses through sequence-specific targeting of repressive chromatin states. ZFP57 is required to maintain the post-fertilization DNA methylation memory of parental-origin at genomic imprints along with ZFP445 which is specific for imprints. However, ZFP57 has multiple methylated genomic targets. Here we conduct RNA-seq and ChIP-seq analyses in normal and ZFP57 mutant mouse ES cells to understand the relative importance of ZFP57 at unique and repetitive regions of the genome.ResultsOver 80% of ZFP57 targets are TEs, however, ZFP57 is not essential for their repression. The remaining targets lie within unique imprinted and non-imprinted sequences. Though loss of ZFP57 influences imprinted genes as expected, the majority of unique gene targets lose H3K9me3 with little effect on DNA methylation and very few exhibiting alterations in expression. Comparison with DNA methyltransferase-deleted ES cells (TKO) identifies remarkably similar losses of H3K9me3 and changes in expression, defining regions where H3K9me3 is secondary to DNA methylation. We show that ZFP57 is the principal methylation-sensitive KZFP recruiting KAP1 and H3K9me3 in ES cells. Finally, like imprints, other unique targets of ZFP57 are enriched for germline-derived DNA methylation including oocyte-specific methylation that is resistant to post-fertilisation epigenetic reprogramming.ConclusionOur analyses suggest the evolution of a rare DNA methylation-sensitive KZFP that is not essential for repeat silencing, but whose primary function is to maintain DNA methylation and repressive histone marks at germline derived imprinting control regions.

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ATRX binds to atypical chromatin domains at the 3′ exons of zinc finger genes to preserve H3K9me3 enrichment

Cited by 66 publications

References 76 publications

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Heterochromatin and the molecular mechanisms of ‘parent-of-origin’ effects in animals

Epigenetic regulation of unique genes and repetitive elements by the KRAB zinc finger protein ZFP57

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