Double chromodomains cooperate to recognize the methylated histone H3 tail

Flanagan, John F.; Mi, Li-Zhi; Chruszcz, M.; Cymborowski, M.; Clines, Katrina L.; Kim, Young Chang; Minor, Władek; Rastinejad, Fraydoon; Khorasanizadeh, Sepideh

doi:10.1038/nature04290

Cited by 472 publications

(464 citation statements)

References 26 publications

Supporting

Mentioning

439

Contrasting

Unclassified

Order By: Relevance

“…The H3K4me2/3 mark is recognized by motifs such as the chromo, tudor, PHD and WD40 domains (Ruthenburg et al, 2007). The chromodomains of HP1 (Jacobs and Khorasanizadeh, 2002) and CHD1 (Flanagan et al, 2005;Pray-Grant et al, 2005), and the tudor domains of JMJD2A (Huang et al, 2006), bind preferentially to trimethylated lysines, but also interact with lower methylation states (mono-and di-). In contrast, the tudor domain of 53BP1, can discriminate between the di-and trimethyl state of H4K20, preferring the dimethyl form (Botuyan et al, 2006;Kim et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

et al. 2008

View full text Add to dashboard Cite

Lethal 3 malignant brain tumor 1 (L3MBTL1), a homolog of the Drosophila polycomb tumor suppressor l(3)mbt, contains three tandem MBT repeats (3xMBT) that are critical for transcriptional repression. We recently reported that the 3xMBT repeats interact with mono-and dimethylated lysines in the amino termini of histones H4 and H1b to promote methylation-dependent chromatin compaction. Using a series of histone peptides, we now show that the recognition of mono-and dimethylated lysines in histones H3, H4 and H1.4 (but not their trimethylated or unmodified counterparts) by 3xMBT occurs in the context of a basic environment, requiring a conserved aspartic acid (D355) in the second MBT repeat. Despite the broad range of in vitro binding, the chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20 monomethylation during the cell cycle. Furthermore, transcriptional repression by L3MBTL1 is enhanced by the H4K20 monomethyltransferase PR-SET7 (to which it binds) but not SUV420H1 (an H4K20 trimethylase) or G9a (an H3K9 dimethylase) and knockdown of PR-SET7 decreases H4K20me1 levels and the chromatin association of L3MBTL1. Our studies identify the importance of H4K20 monomethylation and of PR-SET7 for L3MBTL1 function.

show abstract

Section: Introductionmentioning

confidence: 99%

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Indeed, recent studies revealed that methylation of H3R2 by the PRMT6 methyltransferase impedes both H3K4 trimethylation and recruitment of WDR5 (Guccione et al 2007;Hyllus et al 2007). R2 is also important for the recognition of methylated K4 by CHD1 (Flanagan et al 2005). Analysis of WDR5 crystals have shown that while this protein can interact with all forms of methylated K4, it has additional contacts with H3K4me2 via a pair of conventional and unconventional hydrogen bonds.…”

Section: Wd40 Repeat Protein Structurementioning

confidence: 99%

Diverse functions of WD40 repeat proteins in histone recognition: Figure 1.

Suganuma¹,

Pattenden²,

Workman³

2008

Genes Dev.

View full text Add to dashboard Cite

WD40 repeat proteins have been shown to bind the histone H3 tail at the center of their ␤-propeller structure. In contrast, in this issue of Genes & Development, Song and colleagues (pp. 1313-1318) demonstrate that the WD40 repeat protein p55 binds a structured region of H4 through a novel binding pocket on the side of ␤-propeller, illustrating a diversity of histone recognition by WD40 repeat proteins.The association of WD40 repeat proteins with histones and nucleosomes is of increasing interest because of their functions in a variety of histone/chromatin-modifying complexes. In this issue of Genes & Development, Song et al. (2008) solve the crystal structure of p55, a Drosophila seven-WD40-repeat protein. Binding of p55 is shown to be incompatible with the histone fold of H4 and results in a change in H4 structure. The interaction of p55 with H4 is distinct from that of previously characterized WD40 repeat proteins and utilizes a novel binding pocket on the side of the ␤-propeller instead of the center of the propeller. This novel p55-H4 interaction extends the known contacts by which WD40 repeat proteins recognize histones and reveals diversity in the manner in which this important recognition domain functions. WD40 repeat proteins are important for a variety of cellular functionsWD40 repeats were first noted in the ␤-subunit of the heterotrimeric GTP-binding protein (G protein) (Fong et al. 1986). The G protein structure contained seven WD40 repeats. Each repeating unit formed one of seven ␤-propeller blades with four small anti-parallel ␤-sheets built into a toroidal structure with a tapered end and central canal (Wall et al. 1995;Neer and Smith 2000). The conserved core of repeating units contained 44-60 residues that ended with tryptophan (W) and aspartate (D). Since the initial identification of the WD40 repeats, >160 WD40 repeat proteins have been identified, with the majority found in higher eukaryotes (Smith et al. 1999). Each family member has between four and 10 copies of the WD40 repeats. In general, WD40 repeat proteins have been associated with a diverse range of cellular processes, including RNA processing, transcriptional regulation (Williams et al. 1991;Hoey et al. 1993), mitotic spindle formation (de Hostos et al. 1991;Vaisman et al. 1995), regulation of vesicle formation and vesicular trafficking (Pryer et al. 1993), and control of cell division (Feldman et al. 1997).Four WD40 repeat proteins-WDR5, RbBP5, RbAp48/ 46 (each with seven repeats)-and the Drosophila homolog of RbAp48/46, p55, are components of histone-modifying complexes (Fig. 1). WDR5 is associated with SET domain-containing methyltransferases, such as Set1, MLL, MLL2, and MLL3/4 (Wysocka et al. 2005;Dou et al. 2006;Mendjan et al. 2006;Cho et al. 2007). In addition to its role in histone methylation, WDR5 and WDS, the Drosophila homolog of WDR5, are associated with several histone acetyltransferase (HAT) complexes, including the MSL (male-specific lethal) complex (Mendjan et al. 2006); the ATAC (Ada Two A-containing) complex, whi...

show abstract

“…Template structures for the homology modeling of the CHD7 chromoand helicase domains were selected from the protein database using BLAST (Supp . Table S2) [Durr et al, 2005;Flanagan et al, 2005Flanagan et al, , 2007Hauk et al, 2010;Okuda et al, 2007;Thoma et al, 2005]. We used the X-ray structure of the yeast chromatin remodeler Chd1 (3MWY) as a basis for our structural model and for all subsequent analyses, because it shows the chromo-and helicase domains in a single structure [Hauk et al, 2010].…”

Section: Structural Model Of the Chd7 Chromo-and Helicase Domainsmentioning

confidence: 99%

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

et al. 2012

View full text Add to dashboard Cite

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo-and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5 and 3 regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.

show abstract

Double chromodomains cooperate to recognize the methylated histone H3 tail

Cited by 472 publications

References 26 publications

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

Diverse functions of WD40 repeat proteins in histone recognition: Figure 1.

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

Contact Info

Product

Resources

About