ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome

Abstract

ATR-X (alpha thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the patient missense mutations are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, AD-DATRX), indicating its importance. However, the function of ADDATRX has remained elusive. Here we identify ADDATRX as a novel histone H3 binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by H3K4me3. The co-crystal structures of ADDATRX bound to H31–15K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Importantly, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin. Thus, we have discovered a unique histone recognition mechanism underlying the ATR-X etiology.

Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1

“…3 A and B). Such a helical conformation in the H3 tail has not been observed in other histone-binding complexes (7,26), except that a H3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] tail-like peptide inhibitor bound to lysine specific demethylase 1 (LSD1), which bears Met in place of H3-K4, has been reported to form a similar helical structure (27).…”

“…The histone H3 peptides H3 1-10 and H3 1-12 -K9me3 for crystallography and a series of H3 peptides for ITC measurements were purchased from Toray Research Center. Histones H3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and H4 peptides harboring a site-and degree-specific methylated lysine analog were prepared by cysteine alkylation as reported previously (36, 37).…”

“…More recent structural studies have highlighted the combinatorial read out of multiple histone marks by single or tandemly arranged reader modules (7,(9)(10)(11)(12). However, information on the structural basis for cooperative recognition of histone marks by linked heterologous modules is still limited (8).…”

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

“…This comprises a PHDlike zinc finger and an additional C 2 C 2 motif just upstream, which is structurally similar to the GATA1 zinc fingers (Gibbons et al 1997;Argentaro et al 2007) and is highly related to the zinc finger domains of DNA methyltransferases (Argentaro et al 2007). The domain mediates binding to the amino-terminal tail of histone H3 trimethylated at lysine 9 (Dhayalan et al 2011;Eustermann et al 2011;Iwase et al 2011). The functional importance of the ADD segment in ATRX is clear.…”

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

“…Alternatively, ATRX might associate with target chromatin through binding interactions with core/canonical and/or variant histone proteins, or through interactions with specific histone posttranslational modifications, either directly, or in combination with its interacting proteins HP1 (Kourmouli et al, 2005) or MeCP2 (Nan et al, 2007). It was recently demonstrated that the ADD domain of ATRX is able to efficiently bind H3K9me3 (a known heterochromatic mark) specific peptides in the absence of H3K4me3/2, due to an inability of the ATRX PHD finger domain to recognize and bind H3K4me3 (Dhayalan et al, 2011;Eustermann et al, 2011;Iwase et al, 2011). Currently, it is unclear if other adjacent chemical modifications of nucleosomes, such as H3S10p, a mark that is dramatically induced in the adult CNS in response to environmental stimulation, can impact ATRX localization in chromatin; however, given the combinatorial nature of histone modifications in vivo, it is likely that other mechanisms of ATRX recruitment/displacement will be identified.…”