Structural basis of H2A.Z recognition and H4K20 methylation by SUV420H2
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ABSTRACT:
PROVIDER: PRJNA864759 | ENA |
REPOSITORIES: ENA
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Project description:DNA replication ensures the accurate transmission of genetic information during cell cycle. The interaction between histone methyltransferase SUV420H1 and histone variant H2A.Z plays a critical role in the licensing of early replication origins. However, the mechanism by which SUV420H1 preferentially recognizes H2A.Z-nucleosome and deposits H4 lysine 20 dimethylation (H4K20me2) on DNA replication origins remains elusive. Here, we determined the cryo-EM structures of SUV420H1 bound to H2A.Z-nucleosome or H2A-nucleosome. Our structures show that the SUV420H1 catalytic domain (CD) directly interacts with histone H4 and nucleosomal DNA, whereas a SUV420H1 arginine-rich motif (ARM) anchors to the acidic patch of the nucleosome. The N-terminal aminal acid residues of H4 (Aa 1-24) forms a lasso-shaped structure sandwiched between SUV420H1 CD and nucleosome. The lasso-shaped structure stabilizes the SUV420H1-nucleosome interaction and precisely projects the H4 K20 residue into the SUV420H1 catalytic center. Further analyses revealed a crucial role of SUV420H1 KR-loop (aminal acid residues 214-223), which spatially lies closely to H2A.Z specific residues D97/S98, in dictating the preference for H2A.Z-nucleosome. SUV420H1 K219A/R220A mutations reduced the activity of SUV420H1 for H4K20me2 modification, the preference of SUV420H1 for H2A.Z-nucleosome, and the efficiency of DNA replication initiation. Collectively, our findings elucidate how SUV420H1 preferentially recognizes H2A.Z-nucleosome to deposit H4K20me2 modification and shed light on therapeutic strategies targeting the DNA replication initiation.
2023-12-04 | GSE210197 | GEO
Project description:Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase
| PRJNA989567 | ENA
Project description:Analysis of breast cancer MDA-MB-231 cells stably over-expressing SUV420H2, a histone H4K20 methyltransferase. Several genes were significantly up- or down-regulated. Results provide insight into the molecular mechanism by which H4K20me3 contributes to gene expression. SUV420H2 stably over-expressing MDA-MB-231 cells were cloned. Then total RNA was extracted from the SUV420H2 over-expressing cells and the parental MDA-MB-231 cells.
2015-04-15 | E-GEOD-55947 | biostudies-arrayexpress
Project description:Analysis of breast cancer MDA-MB-231 cells stably over-expressing SUV420H2, a histone H4K20 methyltransferase. Several genes were significantly up- or down-regulated. Results provide insight into the molecular mechanism by which H4K20me3 contributes to gene expression. SUV420H2 stably over-expressing MDA-MB-231 cells were cloned. Then total RNA was extracted from the SUV420H2 over-expressing cells and the parental MDA-MB-231 cells.
2015-04-15 | E-GEOD-56912 | biostudies-arrayexpress
Project description:Here we report the cryo-electron microscopy (cryo-EM) structures of SUV420H1 associated with canonical nucleosome core particles (NCPs) or H2AZ containing NCPs. We find that SUV420H1 shows conformational change after bound to a nucleosome and make extensive site-specific contacts with histone and DNA regions, thus enabling H4K20 insertion for catalysis specifically. Through in vivo functional analysis, we validated special residues of SUV420H1 that are critical for its catalytic activity and function in chromatin state regulation.Thus, our study provides molecular insights into the nucleosome-based recognition and histone- methylation mechanisms of SUV420H1.
2023-12-04 | GSE236249 | GEO
Project description:Analysis of breast cancer MDA-MB-231 cells stably over-expressing SUV420H2, a histone H4K20 methyltransferase. Several genes were significantly up- or down-regulated. Results provide insight into the molecular mechanism by which H4K20me3 contributes to gene expression.
2015-04-15 | GSE55947 | GEO
Project description:Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Epigenetic regulation has emerged as a key mechanism underlying BAT development and function. To study the epigenetic regulation of BAT thermogenesis, we surveyed the expression of epigenetic enzymes that catalyze histone modifications in developmental beige adipocytes and found a unique expression pattern of suppressor of variegation 4-20 homolog 2 (Drosophila) (Suv420h2), a histone methyltransferase that preferentially catalyzes the tri-methylation at histone H4 lysine 20 (H4K20me3), a hallmark of gene silencing. Here we discovered that Suv420h2 expression parallels that of UCP1 expression in brown and beige adipocytes and that SUV420H2 knockdown significantly reduces, whereas SUV420H2 overexpression significantly increases UCP1 levels in brown adipocytes. Suv420h2 knockout (H2KO mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study showed that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) promoter, leading to down-regulated expression of 4E-BP1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
2024-05-09 | GSE244457 | GEO
Project description:Analysis of breast cancer MDA-MB-231 cells stably over-expressing SUV420H2, a histone H4K20 methyltransferase. Several genes were significantly up- or down-regulated. Results provide insight into the molecular mechanism by which H4K20me3 contributes to gene expression.
2015-04-15 | GSE56912 | GEO
Project description:Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Epigenetic regulation has emerged as a key mechanism underlying BAT development and function. To study the epigenetic regulation of BAT thermogenesis, we surveyed the expression of epigenetic enzymes that catalyze histone modifications in developmental beige adipocytes and found a unique expression pattern of suppressor of variegation 4-20 homolog 2 (Drosophila) (Suv420h2), a histone methyltransferase that preferentially catalyzes the tri-methylation at histone H4 lysine 20 (H4K20me3), a hallmark of gene silencing. Here we discovered that Suv420h2 expression parallels that of UCP1 expression in brown and beige adipocytes and that SUV420H2 knockdown significantly reduces, whereas SUV420H2 overexpression significantly increases UCP1 levels in brown adipocytes. Suv420h2 knockout (H2KO mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study showed that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) promoter, leading to down-regulated expression of 4E-BP1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
2024-05-09 | GSE245509 | GEO
Project description:Epigenetic processes regulating gene expression contribute markedly to epithelial cell plasticity in colorectal carcinogenesis. The lysine methyltransferase SUV420H2 comprises an important regulator of epithelial plasticity and is primarily responsible for trimethylation of H4K20 (H4K20me3). Loss of H4K20me3 has been suggested as a hallmark of human cancer due to its interaction with DNMT1. However, the role of Suv4-20h2 in colorectal cancer is unknown.
2022-11-09 | GSE217265 | GEO