Perceiving the epigenetic landscape through histone readers

Musselman, Catherine A.; Lalonde, Marie-Eve; Côté, Jacques; Kutateladze, Tatiana G.

doi:10.1038/nsmb.2436

Cited by 735 publications

(680 citation statements)

References 150 publications

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“…A number of domains bind methylated histone tails. Prominent examples include the chromodomain, Tudor domain, MBT domain, PWWP domain, and PHD domain (4,6,7). The CW domain has recently been identified as a new member of the lysine methylation reader family (8 -11).…”

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confidence: 99%

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Liu

Tempel

Zhang

et al. 2016

Journal of Biological Chemistry

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Covalent modifications of histone N-terminal tails play a critical role in regulating chromatin structure and controlling gene expression. These modifications are controlled by histone-modifying enzymes and read out by histone-binding proteins. Numerous proteins have been identified as histone modification readers. Here we report the family-wide characterization of histone binding abilities of human CW domain-containing proteins. We demonstrate that the CW domains in ZCWPW2 and MORC3/4 selectively recognize histone H3 trimethylated at Lys-4, similar to ZCWPW1 reported previously, while the MORC1/2 and LSD2 lack histone H3 Lys-4 binding ability. Our crystal structures of the CW domains of ZCWPW2 and MORC3 in complex with the histone H3 trimethylated at Lys-4 peptide reveal the molecular basis of this interaction. In each complex, two tryptophan residues in the CW domain form the "floor" and "right wall," respectively, of the methyllysine recognition cage. Our mutation results based on ZCWPW2 reveal that the right wall tryptophan residue is essential for binding, and the floor tryptophan residue enhances binding affinity. Our structural and mutational analysis highlights the conserved roles of the cage residues of CW domain across the histone methyllysine binders but also suggests why some CW domains lack histone binding ability.Chromatin structure is dynamically regulated by histone post-translational modifications, such as methylation, acetylation, phosphorylation, ubiquitination, and sumoylation (1). These post-translational modifications constitute the "histone code," which is written or erased by histone-modifying enzymes and recognized by histone code "reader" proteins (2-4).Histone methylation, such as lysine methylation at the ⑀-amino group at levels from mono-to trimethylation (me1-me3), has received extensive attention (5). A number of domains bind methylated histone tails. Prominent examples include the chromodomain, Tudor domain, MBT domain, PWWP domain, and PHD domain (4, 6, 7). The CW domain has recently been identified as a new member of the lysine methylation reader family (8 -11).The CW domain is a zinc binding domain, composed of ϳ50 amino acid residues with four conserved cysteine (C) and two conserved tryptophan (W) residues, and its name was derived from these conserved residues. CW domains are found in chromatin-associated proteins in animals and plants and grouped into 12 families based on sequence similarity (12). There are seven CW domain-containing proteins in humans, namely ZCWPW1, ZCWPW2, MORC1, MORC2, MORC3, MORC4, and LSD2 (Fig. 1A). Prior studies have shown that the CW domains of ZCWPW1 (8), MORC3 (10), and MORC4 (9) are readers of H3K4 3 methylated histones with differing preferences for histone H3K4 methylation states (i.e. ZCWPW1 and MORC3 preferentially recognize histone H3K4me3 (8, 10), whereas the CW domain of human MORC4 prefers dimethylated H3K4 (9)). The LSD2 CW domain is required for the demethylation function of LSD2 but does not bind to any H3K4 peptides (13). However, th...

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confidence: 99%

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Liu

Tempel

Zhang

et al. 2016

Journal of Biological Chemistry

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“…Individual histone modifications in the vicinity of the binding may substantially alter the binding affinity of the enzyme complex or its formation. This crosstalk has been repeatedly demonstrated within histones, among histones of the same nucleosome (Wang and Patel, 2011;Lindroth et al, 2004;Fuchs et al, 2011;Ruthenburg et al, 2011), and among histones of neighboring nucleosomes (for an overview, see Musselman et al, 2012). Even for single domain proteins, the presence of multiple modifications may be required for binding (Morinière et al, 2009).…”

Section: Chromatin Enzymes As Rewriting Rulesmentioning

confidence: 95%

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

Arnold

Stadler

Prohaska

2013

Journal of Theoretical Biology

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Eukaryotic histones carry a diverse set of specific chemical modifications that accumulate over the life-time of a cell and have a crucial impact on the cell state in general and the transcriptional program in particular. Replication constitutes a dramatic disruption of the chromatin states that effectively amounts to partial erasure of stored information. To preserve its epigenetic state the cell reconstructs (at least part of) the histone modifications by means of processes that are still very poorly understood. A plausible hypothesis is that the different combinations of reader and writer domains in histone-modifying enzymes implement local rewriting rules that are capable of "recomputing" the desired parental modification patterns on the basis of the partial information contained in that half of the nucleosomes that predate replication.To test whether such a mechanism is theoretically feasible, we have developed a flexible stochastic simulation system (available at http://www.bioinf.uni-leipzig.de/Software/StoChDyn) for studying the dynamics of histone modification states. The implementation is based on Gillespie's approach, i.e., it models the master equation of a detailed chemical model. It is efficient enough to use an evolutionary algorithm to find patterns across multiple cell divisions with high accuracy.We found that it is easy to evolve a system of enzymes that can maintain a particular chromatin state roughly stable, even without explicit boundary elements separating differentially modified chromatin domains. However, the success of this task depends on several previously unanticipated factors, such as the length of the initial state, the specific pattern that should be maintained, the time between replications, and chemical parameters such as enzymatic binding and dissociation rates. All these factors also influence the accumulation of errors in the wake of cell divisions.

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“…It is thought that these writers, erasers, and readers work in concert to establish and regulate histone PTM-mediated functions. Finally, histone modifications can further act in combinations to recruit or repel different binding proteins, or cross-regulate one another through complex pathways [114][115][116]. In this review, we will focus on some of the most recent advances in both well-known and newly discovered histone PTMs (Table 1).…”

Section: Histone Modificationsmentioning

confidence: 99%

“…In this review, we will focus on some of the most recent advances in both well-known and newly discovered histone PTMs (Table 1). Given the broad and complex scope of this field and due to limited space for this review, we refer interested readers to additional reviews for further reading [114][115][116][137][138][139].…”

Section: Histone Modificationsmentioning

confidence: 99%

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

2015

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The eukaryotic genome is highly complex and compartmentalized into distinct physical and functional domains. Although the majority of genomic DNA is wrapped around histone proteins in the same manner to form repeating units of nucleosomes, the use of distinct histone variants and the myriad of posttranslational modifications (PTMs) on different histones and amino acid residues create great diversity among these nucleosomes. In this review, we summarize some of the most recent findings in the histone variant and PTM fields and update the readers on our current understanding of various histone-related pathways. Furthermore, we discuss how homotypic or heterotypic deposition of histone variants as well as symmetric or asymmetric histone PTMs within the nucleosome context can further expand the diversity and functionality of chromatin. Altogether, this review highlights the complexity of chromatin composition and organization and their regulatory functions within the eukaryotic genome.

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Perceiving the epigenetic landscape through histone readers

Cited by 735 publications

References 150 publications

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

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