Histone H2A isoforms: Potential implications in epigenome plasticity and diseases in eukaryotes

Shah, Sanket; Verma, Tripti; Rashid, Mudasir; Gadewal, Nikhil; Gupta, Sanjay

doi:10.1007/s12038-019-9985-0

Cited by 11 publications

(10 citation statements)

References 52 publications

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“…The H2A lysine targets of BRCA1/BARD1 are in a flexible region of the C-terminal tail that is not observed by density in our structure. This region is less conserved between isoforms than ordered regions of the histone 41 ( Fig. 5a ).…”

Section: Resultsmentioning

confidence: 99%

BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1

Witus

Burrell

Farrell

et al. 2021

Nat Struct Mol Biol

138

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Mutations in BRCA1/BARD1’s E3 ubiquitin ligase RING domains predispose carriers to breast and ovarian cancers. We present the first structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the complex selectively ubiquitylates lysines 125/127/129 in the flexible C-terminal tail of H2A in a fully human system. The structure reveals that a novel BARD1-histone interface couples to a repositioning of UbcH5c compared to the structurally similar PRC1 E3 ligase Ring1b/Bmi1 that ubiquitylates H2A Lys119 in nucleosomes. This interface is sensitive to both H3 Lys79 methylation status and mutations found in cancer patients. Furthermore, NMR reveals an unexpected mode of E3-mediated substrate regulation through modulation of dynamics in the C-terminal tail of H2A. Our findings provide insight into how E3 ligases preferentially target nearby lysine residues in nucleosomes by a steric occlusion and distancing mechanism.

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Section: Resultsmentioning

confidence: 99%

BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1

Witus

Burrell

Farrell

et al. 2021

Nat Struct Mol Biol

138

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“…The outputs are represented as a heatmap of histone H2A-H2B dimer with their potential energy. Earlier studies from our lab have shown that the nucleosomal stability of H2A1H/H2B was different compared to H2A.2/H2B, in silico as well as in vitro [48,49]. At the dimer level also the stability was different for both the isoforms.…”

Section: Histone Dimer Stability Prediction For Histone H2a and H2b Imentioning

confidence: 76%

HISTome2: a database of histone proteins, modifiers for multiple organisms and epidrugs

Shah

Mandloi

Kunte

et al. 2020

Epigenetics & Chromatin

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Background: Epigenetics research is progressing in basic, pre-clinical and clinical studies using various model systems. Hence, updating the knowledge and integration of biological data emerging from in silico, in vitro and in vivo studies for different epigenetic factors is essential. Moreover, new drugs are being discovered which target various epigenetic proteins, tested in pre-clinical studies, clinical trials and approved by the FDA. It brings distinct challenges as well as opportunities to update the existing HIstome database for implementing and applying enormous data for biomedical research. Results: HISTome2 focuses on the sub-classification of histone proteins as variants and isoforms, post-translational modifications (PTMs) and modifying enzymes for humans (Homo sapiens), rat (Rattus norvegicus) and mouse (Mus musculus) on one interface for integrative analysis. It contains 232, 267 and 350 entries for histone proteins (noncanonical/variants and canonical/isoforms), PTMs and modifying enzymes respectively for human, rat, and mouse. Around 200 EpiDrugs for various classes of epigenetic modifiers, their clinical trial status, and pharmacological relevance have been provided in HISTome2. The additional features like 'Clustal omega' for multiple sequence alignment, link to 'FireBrowse' to visualize TCGA expression data and 'TargetScanHuman' for miRNA targets have been included in the database. Conclusion: The information for multiple organisms and EpiDrugs on a common platform will accelerate the understanding and future development of drugs. Overall, HISTome2 has significantly increased the extent and diversity of its content which will serve as a 'knowledge Infobase' for biologists, pharmacologists, and clinicians. HISTome2: The HISTone Infobase is freely available on http://www.actre c.gov.in/histo me2/.

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“…Previously our lab has shown the molecular basis of H2A isoforms in regulating nucleosome stability to attain a physiological state (Bhattacharya et al, 2018). In continuation, the lab has shown in silico differential nucleosomal stability of different H2A isoforms that differ among themselves by few amino acids (Shah et al, 2020). Therefore, the tissue-specific expression and incorporation of H2A isoforms in genomic regions may provide specific nucleosomal organization for defining cell fate.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our study has shown advances in the complexity of eukaryotic H2A isoforms, their roles in defining nucleosome organization, and their association with diseases (Shah et al, 2020). H2A isoform family consists of 16 genes and codes for 11 proteins (Singh et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of H2A isoforms contribute to tissue and lineage specificity with HIST2H2AC as a potential cancer biomarker

Shah

Rashid

Natu

et al. 2021

Preprint

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Recent advancements in the field of histone biology imply non-redundancy in the function of histone H2A isoforms; however, the expression of H2A isoforms in various normal tissue types, the correlation among organs and tumor/tumor type-specific expression remain poorly investigated. The profiling of sixteen H2A isoforms in eleven different normal human tissue types strongly suggests their tissue-specific or predominant expression. Further, clustering analysis shows a lineage-specific correlation of H2A isoforms. In continuation, the expression analysis in twelve human tumor types shows overexpression of HIST2H2AC. Moreover, overexpression was observed exclusively in tumor samples but not with fetal samples; highlighting the cancer-specific association of HIST2H2AC. Further, in silico analysis of TCGA pan-cancer data also showed tumor-specific over-expression of the HIST2H2AC isoform. Our findings provide insights into tissue-type-specificity of histone H2A isoforms expression patterns and advance our understanding of their importance in lineage specification and cancer.

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Histone H2A isoforms: Potential implications in epigenome plasticity and diseases in eukaryotes

Cited by 11 publications

References 52 publications

BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1

BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1

HISTome2: a database of histone proteins, modifiers for multiple organisms and epidrugs

Differential expression of H2A isoforms contribute to tissue and lineage specificity with HIST2H2AC as a potential cancer biomarker

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