Allosteric Regulation of Chromatin-Modifying Enzymes - Biochemistry

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Allosteric Regulation of Chromatin-Modifying Enzymes Jung-Ae Kim, Minjung Kwon, and Jaehoon Kim Biochemistry, Just Accepted Manuscript • DOI: 10.1021/acs.biochem.8b00894 • Publication Date (Web): 17 Oct 2018 Downloaded from http://pubs.acs.org on October 20, 2018

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Biochemistry

Allosteric Regulation of Chromatin-Modifying Enzymes Jung-Ae Kim,,1,2 Minjung Kwon3 and Jaehoon Kim,3 1Personalized

Genomic Medicine Research Center, Korea Research Institute of Bioscience and

Biotechnology, Daejeon 34141, South Korea 2Department

of Functional Genomics, KRIBB School of Bioscience, University of Science and

Technology, Daejeon 34113, South Korea 3Department

of Biological Sciences, Korea Advanced Institute of Science and Technology,

Daejeon 34141, South Korea Address

correspondence to:

Jaehoon Kim, Ph.D. Tel: +82-42-350-2632 Fax: +82-42-350-2610 E-mail: [email protected] Jung-Ae Kim, Ph.D. Tel: +82-42-879-8129 Fax: +82-42-879-8119 E-mail: [email protected]

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ABSTRACT Dynamic changes in chromatin structure are crucial for diverse biological processes. Given the complexity of the epigenetic landscape, understanding the specificity of chromatin modification has been a major interest in the epigenetics field. Recent progress in biochemical and structural analyses in the field of chromatin biology has revealed that recognition of allosteric effectors and subsequent conformational change(s) are central to the regulation of catalytic activities and functions of chromatin-modifying enzymes. Here, we review several examples of distinctive nucleosome features, including DNA methylation, histone modifications and variable-length linker DNA, that allosterically regulate the enzymatic activities of chromatin modifiers to confer functional specificity in a given chromatin context. We further highlight the biological significance of these allosteric mechanisms and discuss their potential as emerging targets for selective modulation of chromatin architecture.


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Biochemistry

INTRODUCTION The epigenetic landscape (also known as Waddington landscape) is a well-known concept that illustrates how cells determine their identity without a change in primary genetic information— the DNA sequence. Alterations in chromatin structure by DNA methylation, various posttranslational modifications of histone proteins, as well as changes in nucleosome density and spacing produce different epigenetic landscapes. An important function of chromatin alterations is to regulate gene expression. Methylation at cytosine bases of promoter DNA represses transcription of the corresponding genes.1 Post-translational modifications of histone proteins and/or different nucleosome deposition patterns are also closely associated with gene expression.2-4 Accumulating evidence has revealed diverse molecular mechanisms by which individual alterations in chromatin structure are regulated. A subject of particularly intense research interest is how the specificity of chromatin regulation is achieved. Many chromatin modifiers contain multiple chromatin ‘reader’ domains, which recognize DNA/histone modifications and serve as a platform for binding to particular target regions. Accordingly, recruitment of chromatin modifiers through physical interactions between reader domains and DNA/histone modifications underlies

an

important

mechanism

for

specifying

chromatin

alterations.4

Moreover,

combinatorial binding via multiple reader domains has been suggested as an efficient mechanism for fine-tuning the specificity and efficiency of targeting chromatin modifiers.5,6 However, in some cases, defects in reader domains have little or only modest effects on the chromatin targeting of modifiers, indicating that the specificity of chromatin alterations is not solely explained by the recruitment of chromatin modifiers.7-9 Recent biochemical and structural analyses employing purified chromatin-modifying enzymes and physiologically relevant nucleosome substrates have demonstrated that necessary enzyme activities are indeed affected by particular nucleosome components, such as modifications of DNA/histones and the length of linker DNA. These observations suggest the possibility that reader domains function as allosteric effector sensors and thereby affect the catalytic activities of chromatin modifiers. Allosteric regulation is the process of modulating the activities of biological macromolecules by transmitting the effect of binding at one site to another, often distal, functional site.10 In addition, the conformational changes induced by an allosteric entity, for example through effector binding, are reversible.11 In this regard, DNA/histone modifications that are able to function as allosteric 3 ACS Paragon Plus Environment

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effectors confer catalytically active states on chromatin modifiers and thereby generate specific epigenetic landscapes in target loci. Here, in an effort to provide a better understanding of how a specific epigenetic landscape is established and maintained, we review recent examples of allosteric regulatory mechanisms of chromatin-modifying enzymes (Table 1). We further discuss targeting allosteric mechanisms that regulate chromatin-modifiers as a promising approach for re-shaping epigenetic landscapes. Table 1. Nucleosome components involved as allosteric effectors of the catalytic activity of chromatin-modifiers. Allosteric Effectors

Chromatin Modifiers

Effector Sensing Domains/Subunits

Functions

References

DNMT3A

ADD domain of DNMT3A

DNA methylation

(18,19)

KDM5A

PHD1 domain of KDM5A

H3K4 demethylation

(43)

H3K27me3

PRC2

EED

H3K27 methylation

(31)

H3K36me3

Rpd3S

Eaf3

Histone deacetylation

(51)

Rpd3S

Not determined

Histone deacetylation

(50)

ISWI

HSS and NegC domains of ISWI

Nucleosome spacing

(53,54)

ACF

ACF1

Nucleosome spacing

(56)

ISWI

AutoN domain of ISWI

Nucleosome spacing

(54,55)

ACF

ACF1

Nucleosome spacing

(56)

Chd1

Chromodomains of Chd1

Nucleosome remodeling

(59)

Nucleosome density

PRC2

SUZ12

H3K27 methylation

(34)

H3K4me3

PRC2

RbAp48

H3K27 methylation

(33)

H3K36me2/3

PRC2

RbAp48

H3K27 methylation

(33)

H3K4me0

Activators

Length of linker DNA

N-terminal tail of H4

Inhibitors


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Biochemistry

ALLOSTERIC REGULATION OF DNA METHYLATION DNA methyltransferases (DNMTs) establish and maintain methylations at cytosine bases in DNA. There are three enzymatically active DNMTs in human cells, DNMT1, DNMT3A and DNMT3B, each of which possesses a multiple-domain architecture (Figure 1A). Whereas DNMT1 ensures maintenance of methylation throughout DNA replication, DNMT3A and DNMT3B establish de novo methylation.12 In addition to these universal DNMTs, it was recently reported that some rodent species possess DNMT3C as an additional de novo DNMT.13 Genomic profiling studies have revealed a close connection between DNA methylation and histone modifications, suggesting a histone-guided mechanism for the establishment of DNA methylation.1,14 Both DNMT3A and DNMT3B contain ADD (ATRX-DNMT3-DNMT3L) and PWWP (Pro-Trp-Trp-Pro) domains. Supporting a histone-modification–mediated targeting pathway, the PWWP domain of DNMT3B, which enables binding to lysine 36 tri-methylated histone H3 (H3K36me3)15, facilitates the recruitment of DNMT3B to transcribed gene bodies that are enriched with SET2-mediated H3K36me3 modifications.16 However, despite possessing a similar PWWP domain capable of binding to H3K36me3 in vitro17, the genomic targeting of DNMT3A is not dependent on H3K36me3. Instead, recognition of unmethylated H3 at lysine 4 (H3K4me0) by the ADD domain of DNMT3A is crucial for the function of DNMT3A.18,19 Biochemical assays have shown that the enzymatic activity of DNMT3A is stimulated by H3K4me0, either in the form of free peptide or within a nucleosome, but not by H3K4me3.19,20 A structural analysis found that the DNA-binding ability of the DNMT3A catalytic domain is inhibited by intramolecular physical interactions with the ADD domain. However, binding to the histone N-terminal tail containing H3K4me0 induces a large movement of the ADD domain that disrupts the interaction with the catalytic domain and thus releases the auto-inhibition of DNMT3A.19 This finding indicates that H3K4me0 functions as an allosteric activator of DNMT3A, explaining the mechanism underlying the negative correlation of H3K4me3 with DNA methylation. Unlike de novo methyltransferases, DNMT1 is largely localized to DNA replication foci during Sphase and preferentially methylates hemimethylated CpG (HeDNA) dinucleotides.21 Several early studies showed that binding of methylated DNA to the N-terminal part of DNMT1 encompassing a CXXC motif induces an allosteric change that stimulates methylation activity toward unmethylated DNA.22 However, the precise molecular mechanism underlying this allosteric modulation of DNMT1, including the specific binding region that recognizes methylated 5 ACS Paragon Plus Environment

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DNA other than the catalytic domain, has remained unclear. Instead, more recent studies point to UHRF1 (ubiquitin-like, containing PHD and RING fingers domain 1), a multi-domain– containing, DNMT1-associating subunit, as the DNMT1 complex component subject to allosteric regulation by sensing HeDNA to regulate the maintenance of DNA methylation during DNA replication.23 Ubiquitylation at H3K23 mediated by the RING-finger domain of UHRF1 is essential for recruitment of DNMT1 to DNA replication sites.24 This would imply that ubiquitylated H3K23 serves as a binding platform for DNMT1. In addition, the SRA (SET and RING finger-associated domain) domain of UHRF1 binds to HeDNA with modest selectivity.22 Interestingly, a biochemical characterization study showed that physical association of the SRA domain with HeDNA robustly increases the ubiquitylation activity of UHRF1 toward H3K23.25 As a result, DNMT1 is retained at hemi-methylated regions enriched with ubiquitylated H3. An independent structural study showed that UHRF1 intrinsically adopts a closed conformation through an intramolecular interaction between the spacer region adjacent to the SRA domain and the TTD (tandem-Tudor domain), and by binding of the SRA domain to the PHD (plant homeodomain), which block recognition of H3K9me3 and H3R2me0, respectively.26 By contrast, the recognition of HeDNA by the SRA domain disrupts these inhibitory intramolecular interactions and promotes an open conformation that recognizes H3K9me3 and facilitates UHRF1-DNMT1 interactions. The intramolecular interaction that occludes binding of UHRF1 to chromatin is also perturbed by the physical association of USP7 (ubiquitin-specific-processing protease 7) to UHRF1 that releases the TTD domain of UHRF1 for nucleosome binding.27 Taken together, these studies demonstrate that HeDNA functions as an allosteric activator that induces a conformation change in UHRF1, a dynamic binding partner of DNMT1, and consequently promotes DNA methylation (Figure 1B).


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Biochemistry

Figure 1. Allosteric regulation of DNA methylation. (A) Domain architecture of human DNMT proteins. Domains within DNMT1, DNMT3A, and DNMT3B are denoted as follows: DMAPD, DNA methyltransferase associated protein 1 interacting domain; NLS, nuclear localization signal; RFTS; replication foci targeting sequence; CXXC, CXXC domain; BAH, bromo-adjacent homology domain; PWWP, Pro-Trp-Trp-Pro motif; and ADD, ATRX-DNMT3-DNMT3L domain. (B) Schematic depiction of the allosteric mechanism by which UHRF1 translates sensing of HeDNA to stimulation of DNMT1 activity towards chromatin regions enriched with HeDNA and H3K9me3. Domains within UHRF1 are denoted as follows: UBL, ubiquitin-like; TTD, tandem-Tudor domain; PHD, plant homeodomain; SRA, SET and RING finger-associated domain; and RING, really interesting new gene. Inhibitory effects on DNMT1 activity are denoted in blue, whereas allosteric stimulatory effects on DNMT1 activity are marked in red. ALLOSTERIC REGULATION OF HISTONE MODIFICATIONS PRC2–Mediated H3K27me3 Modifications Are Regulated by Multiple Allosteric Effectors. PRC2 (polycomb repressive complex 2) is responsible for the mono-, di- and tri-methylation of H3 at lysine 27 (H3K27me1/2/3). The histone lysine methyltransferase (HMT) activity of PRC2 resides in the SET (Su(var)3-9, Enhancer-of-zeste, and Trithorax) domain-containing proteins EZH1 (enhancer of zeste 1 polycomb repressive complex 2 subunit) and EZH2.28 However, the HMT activity of PRC2 requires the additional subunits, EED, SUZ12 and RbAp48 (Figure 2A). Interestingly, whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze H3K27me1/2, only PRC2-EZH2 can be strongly activated by allosteric modulators to catalyze H3K27me3.9 These distinct regulatory mechanisms suggest that the two PRC2 complexes display differential 7 ACS Paragon Plus Environment

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responses to a given epigenetic environment, such as tissue specificity and developmental stage. Recent structural analyses of fungal and human PRC229,30 have revealed that PRC2-EZH2 undergoes a structural interconversion between different catalytic states. The catalytic SET domain of EZH2 itself exhibits an auto-inhibitory state with an inaccessible substrate-binding surface and an incomplete cofactor-binding pocket. However, upon association with EED and SUZ12, the EZH2-EED-SUZ12 ternary complex generates a conformational change in the catalytic region encompassing the SET domain that relieves its auto-inhibition and confers enzymatic activity on EZH2. Nucleosomal features such as H3K27me3 impart additional regulatory effects on local and global conformational changes in PRC2 that result in distinct catalytic outputs. Binding of H3K27me3 to the aromatic cage of EED is largely responsible for stimulating the enzymatic activity of PRC2, giving rise to a model for the propagation of H3K27me3 marks along repressive chromatin domains.31 The crystal structure of the H3K27me3-bound PRC2 ternary complex shows that the H3K27me3 peptide is sandwiched between EED and the SRM (stimulation-responsive motif) of EZH2, which is highly flexible in the absence of the stimulating H3K27me3 peptide.29 This suggests the possibility that the SRM functions to provide an allosteric pathway for transmitting the signal from H3K27me3-bound EED to the catalytic SET domain of EZH2. In support of this, mutations in the EZH2-SRM domain or EED have been shown to decrease the H3K27me3-mediated stimulatory activity of PRC2 in vitro and reduce H3K27me2/3 levels in embryonic stem cells, with little effect on chromatin association of PRC2.9,29 Similar to H3K27me3, tri-methylation of Jarid2 (Jarid2-me3), a PRC2-interacting protein, promotes the catalytic activity of PRC2 by binding to the EED subunit.32 The allosteric effect of Jarid2-me3 also reflects stabilization of the SRM of EZH2.30 Thus, Jarid2 methylation is suggested to promote PRC2 activity at chromatin regions devoid of prior H3K27me3 modifications (Figure 2B,C).


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Biochemistry

Figure 2. Allosteric regulation of PRC2-mediated H3K27me3 modifications. (A) Domain architectures of human PRC2 subunits. Domains within EZH2, EED, SUZ12, and RbAp48 are denoted as follows: EBD, EED binding domain; SRM, stimulation-responsive motif; SANT, Swi3/Ada2/N-Cor/TFIIIB domain; CXC, cysteine-rich domain; SET, Su(var)3-9, Enhancer-of-zeste, and Trithorax; WD, WD40 domain; Zn, Zinc finger; and VEFS, VRN2-EMF2FIS2-Su(z)12. (B) Recognition of H3K27me3 or Jarid2-me3 by the EED results in a conformational change in the PRC2 catalytic core. The SRM domain of EZH2 is repositioned to form a stable sandwich-like structure with EED-H3K27me3/Jarid2-me3, which enables transmission of the allosteric signal to the catalytic SET domain. (C) Coordination of different allosteric effectors in the regulation of PRC2 catalytic activity. Allosteric inhibitory effects on activity are denoted in blue, whereas allosteric activation effects are marked in red. Unlike H3K27me3, the active transcription marks, H3K4me3 and H3K36me2/3 inhibit the HMT activity of PRC2. Biochemical and structural analyses of Drosophila PRC2 have revealed that the PRC2 submodule, consisting of Nurf55 and Su(z)12 (Drosophila homologs of RbAp48 and SUZ12, respectively), binds to the N-terminus of H3.33 H3K4me3 modification decreases the binding affinity of the submodule for the H3 peptide, without affecting nucleosome binding of PRC2. The HMT activity of PRC2 is reduced by more than 50% in H3K4me3-containing nucleosomes compared with that in unmodified nucleosomes. These observations demonstrate 9 ACS Paragon Plus Environment

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that H3K4me3 inhibits the HMT activity of PRC2, not by causing a defect in nucleosome binding, but rather by reducing catalytic turnover. H3K36me2/3 modifications also exert a similar inhibitory effect on the HMT activity of PRC2 toward nucleosome substrates.33 Collectively, H3K4me3 and H3K36me2/3, which are associated with active transcription, appear to function as allosteric inhibitors of PRC2 catalytic function (Figure 2C). It has also been found that the density of nucleosome arrays is a critical modulator of PRC2 activity.34 A region of H3 (alanine 31 to arginine 42) from neighboring nucleosomes activates the catalytic activity of Drosophila PRC2. Protein cross-linking experiments and systemic mutational analyses have found that evolutionary conserved regions in Su(z)12 encompassing resides 507 to 630 are responsible for the allosteric effect of the H3 peptide on PRC2 activity. In addition, unlike the case with its wild-type counterpart, ectopic expression of SUZ12 mutated at the same residues fails to rescue the deficiency in H3K27me3 modifications in SUZ12-null mouse embryonic stem (ES) cells. This suggests that allosteric activation of PRC2 by the neighboring nucleosome is important for its in vivo function. A kinetic analysis of the retinoic acid-inducible region in mouse ES cells demonstrated that local chromatin compaction precedes the establishment of H3K27me3 marks. Together, these findings suggest that, in addition to active histone modification marks such as H3K4me3 and H3K36me2/3, a lower nucleosome density in actively transcribing regions functions as an additional important modulator that attenuates PRC2 activity, whereas H3K27me3 and Jarid2-me3 function as allosteric activators of PRC2 (Figure 2C). H4R17me1 Marks Stimulate PRMT5-Mediated H4R3me2s Modifications. Like lysine methylation, arginine methylation functions in gene regulation by generating activating or repressive histone modification marks.35 There are three main forms of arginine methylation, mono-methylation, asymmetric di-methylation and symmetric di-methylation, each of which often serves distinctive functions. For example, asymmetric di-methylation of histone H4 at arginine 3 (H4R3me2a) is associated with active transcription, whereas symmetric dimethylation of H4 at the same residue (H4R3me2s) is linked to transcriptional repression. The protein arginine methyltransferase (PRMT) family proteins responsible for these methylations fall into three families: types I, II and III. Types I and II enzymes generate mono-methyl arginine as an intermediate to produce asymmetric and symmetric di-methyl arginine, respectively. By contrast, type III enzymes catalyze only mono-methylation of histones in vitro.36 Among the 10 ACS Paragon Plus Environment

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Biochemistry

different PRMTs, PRMT5 is particularly interesting as its overexpression is frequently observed in different cancers and is involved in promoting cell survival in the face of DNA-damaging anticancer agents.37 PRMT5 is a type II enzyme that is involved in the formation of almost all symmetric di-methyl arginine marks, including H4R3me2s. Biochemical characterizations of this enzyme have revealed that neighboring positively charged residues (H4K5, H4K8, H4K12, H4K16) are important for substrate binding affinity.38 In line with this, acetylation of H4K5 has been shown to increase the H4R3me2s-generating activity of PRMT5.39 Recent kinetic analyses of recombinant PRMT5 complexed with MEP50 (methylosome protein 50) found that PRTM5 catalytic activity displays positive cooperativity (Hill coefficient > 1) in response to different concentrations of H4 peptide substrates.40 This suggests that PRMT5 activity is regulated by an allosteric mechanism. In addition, H4R17me1 marks promote PRMT5 methyltransferase activity toward H4R3, exerting significant effects on its kinetics. In support of this, a decrease in H4R3me2s is observed in cells depleted of PRMT7,35 a type III enzyme responsible for H4R17me1 modifications.41 H4R17me1-mediated allosteric regulation of the catalytic activity of PRMT5 provides an explanation for how PRMT7 functions to modulate H4R3me2s in cells. It is possible that physical recognition of H4R17me1 by the PRMT5/MEP50 complex causes conformational changes in the catalytic region of PRMT5 and thereby increases its activity toward H4R3. Further structural studies will provide molecular details of this regulation. H3K4me0 Marks Promote the Lysine Demethylase Activity of KDM5A. KDM5A (lysine demethylase 5A) is a lysine demethylase that specifically removes H3K4me1/2/3 marks. As a member of the KDM5 subfamily of Jumonji (Jmj) domain-containing lysine demethylases, KDM5A possesses a highly conserved domain architecture that includes one JmjC and three PHD domains (PHD1-3). Of these PHD domains, PHD3 is able to bind to H3K4me3 in the context of a fusion protein with the nucleoporin, NUP98.42 By contrast, PHD1 of KDM5A binds to H3K4me0 produced by KDM5A itself.42,43 Moreover, deletion of PHD1, but not PHD2 or PHD3, has been shown to impair the activity of human and Drosophila KDM5A homologues in vivo, resulting in an increase in cellular H3K4me3 levels.44,45 Biochemical assays employing recombinant KDM5A have shown that the demethylase activity toward all three states of H3K4 methylation on peptide and nucleosome substrates is stimulated by the binding of PHD1 to H3K4me0.43 In addition, mutations of the residues responsible for PHD1 binding to 11 ACS Paragon Plus Environment

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H3K4 N-terminal tail peptides strongly impair the catalytic efficiency of KDM5A. These observations suggest a model in which sensing of H3K4me0 by PHD1 allosterically facilitates the catalytic activity of the JmjC domain. It remains to be determined whether PHD1-mediated H3K4me0 recognition affects the affinity of KDM5A to substrates. Nonetheless, similar to the case for H3K27me3-mediated PRC2 activation, the positive-feedback mechanism of H3K4me0induced catalytic activity of KDM5A is possibly linked to the way in which histone demethylation is propagated through neighboring nucleosomes. Rpd3S-Mediated Histone Deacetylation Is Allosterically Regulated by H3K36me2/3 Marks and the Length of Linker DNA. The yeast Rpd3S histone deacetylase (HDAC) complex carrying the catalytic Rpd3 subunit (Figure 3A) plays a role in suppressing cryptic transcription initiation within coding regions.46 The histone deacetylation activity of Rpd3S is stimulated by recognition of H3K36me3 through two associating subunits: Eaf3, containing a CHD domain, and Rco1, containing PHD domains.47 However, the binding affinities of these domains for modified H3 peptide are weak and less specific.48,49 Instead, Rpd3S has been shown to make histone modificationindependent contacts with nucleosomes.7 Interestingly, Rpd3S exhibits preferential binding and catalytic activity towards di-nucleosome substrates relative to mono-nucleosome substrates. Further, the length of nucleosomal linker DNA affects Rpd3S function.50 When two nucleosomes are within an optimal distance, H3K36me3 on one nucleosome induces the HDAC activity of Rpd3S

toward

the

neighboring

nucleosome.

Biochemical

assays

measuring

hydrogen/deuterium exchange rates at each residue, which correlate with solvent accessibility at the region, have shown that Rpd3S undergoes conformational changes upon contact with nucleosomes.51 This study also showed that the H3K36me3-reading subunit Eaf3 has DNA and histone-binding abilities that are secured in a self-constrained state as an individual subunit. However, when Rpd3S is engaged with nucleosomes through several weak interactions, the SID (Sin3-interacting domain) of Rco1, which directly binds to Eaf3, allosterically activates Eaf3, enabling it to recognize H3K36me3. In addition, the auto-inhibitory mechanism of Eaf3 that limits its binding to DNA is relieved. These observations indicate that a SID-induced conformational change is essential for the HDAC activity of Rpd3S toward H3K36-methylated nucleosomes in vitro and in vivo, identifying the SID domain of Rco1 as a crucial mediator of allosteric regulation within the Rpd3 (Figure 3B).


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Biochemistry

Figure 3. Allosteric regulation of Rpd3S-mediated histone deacetylation toward H3K36me2/3-containing nucleosomes. (A) Domain architectures of the yeast Rpd3S complex subunits involved in allosteric regulation. Domains within Rpd3, Eaf3, and Rco1 are denoted as follows: HDAC, histone deacetylase (catalytic region); CHD, chromodomain; MRG, MRG domain; PHD, plant homeodomain; AID, auto-inhibition domain; and SID, Sin3-interacting domain. (B) Schematic depiction of the allosteric mechanism by which Rpd3S stimulates its HDAC activity toward H3K36me2/3containing nucleosomes. Sequential events in the allosteric regulation of Rpd3S catalytic activity are denoted by arrows and numbers. ALLOSTERIC REGULATION OF NUCLEOSOME POSITIONING BY ATP-DEPENDENT CHROMATIN REMODELERS The N-terminal Tail of H4 and Proper Length of Linker DNA Allosterically Relieve the Auto-Inhibited State of ISWI. ISWI (imitation switch)-family chromatin remodeling enzymes are members of the SWI2/SNF2 ATPase superfamily. The ISWI chromatin remodeler is involved in diverse chromatin-based biological processes, including heterochromatin formation.52 The domain architecture of the 13 ACS Paragon Plus Environment

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ISWI catalytic core, composed of ATPase, AutoN and NegC domains, is evolutionary well conserved (Figure 4A). In addition, ISWI contains an HSS (HAND-SANT-SLIDE) domain at its C-terminus that binds to extranucleosomal linker DNA and whose function is essential for ISWI catalytic activity.53 The catalytic activity of ISWI is sensitive to linker DNA length and requires the N-terminal tail of H4 as a positive regulator. The underlying mechanism of this regulation was revealed by biochemical analyses of a series of ISWI mutants containing mutations in internal domains.54 Point mutations in or deletions of AutoN and NegC domains enabled ISWI to translocate nucleosomes in the absence of the H4 N-terminal tail or linker DNA. Removal of these domains bypassed the requirement of the HSS domain as well. These observations suggest that the inhibitory effects of AutoN and NegC are antagonized by the H4 N-terminal tail and binding of the HSS domain to linker DNA.

Figure 4. Allosteric regulation of ACF-complex–mediated nucleosome spacing. (A) Domain architectures of human ACF complex subunits. Domains within SNF2H and ACF1 are denoted as follows: AutoN, N-terminal autoregulatory domain; NegC, C-terminal negative regulatory domain; HSS, HAND-SANT-SLIDE domain; WAC, WSTF/Acf1/Cbp146; DDT, DNAbinding homeobox and different transcription factors; BAZ, bromodomain adjacent to zinc finger domain; WAKZ, WSTF/Acf1/KIAA0314/ZK783.4 motif; PHD, plant homeodomain; and BRD, bromodomain. (B) Schematic depictions of allosteric mechanism by which the ACF complex regulates ATP-dependent chromatin-remodeling activities. When linker DNA is short, ACF1 preferentially binds to the H4 N-terminal tail and SNF2H is in an intrinsically inactive state owing to intramolecular interactions of the catalytic core domain with AutoN and NegC domains (left). When long linker DNA is recognized by ACF1 and the HSS domain of SNF2H, the H4 Nterminal tail released from ACF1 binds to the catalytic core of SNF2H, relieving the inhibitory interactions between the catalytic domain and AutoN and NegC domains of SNF2H. The consequent conformational change stimulates the catalytic activity of the ACF complex (right). 14 ACS Paragon Plus Environment

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Physical interactions are marked with dashed red lines. The molecular details of this regulation were further revealed by the crystal structure of fungal ISWI in association with an H4 peptide.55 In the absence of nucleosome, both AutoN and NegC domains bind to the catalytic core domain, holding ISWI in a catalytically inactive conformation. The H4 peptide binds to the region within the catalytic core domain, which is coincident with the AutoN-binding site. These observations suggest that the H4 N-terminal tail competes with AutoN for association with the catalytic core of ISWI. By contrast, engagement of the HSS domain of ISWI with long rather than short linker DNA disturbs the binding of NegC to the catalytic core, thereby relieving the inactive conformation. A study of the human ACF (ATP-dependent chromatin assembly and remodeling factor) complex, which comprises SNF2H, a human ISWI homolog, and the accessory subunit ACF1, was shown to extend the allosteric mechanism to include interactions between different subunits in the complex.56 This study showed that ACF1 binds either the H4 N-terminal tail or linker DNA. When the linker DNA on the nucleosomal substrate is short, ACF1 preferentially binds to the H4 N-terminal tail, allowing AutoN to inhibit the ATPase activity of SNF2H. By contrast, as the linker DNA lengthens, ACF1 preferentially binds to the linker DNA and thus releases the H4 Nterminal tail, allowing it to compete with the AutoN domain (Figure 4B). Collectively, these findings indicate that ACF1 is as an allosteric mediator that senses the length of linker DNA and transmits the information to the nucleosome, recalibrating the activity of the ACF complex. The Chromatin-Remodeling Activity of CHD Is Stimulated by the H4 N-terminal Tail and Linker DNA. CHD (chromodomain helicase DNA-binding) family chromatin remodelers also belong to the SWI2/SNF2 ATPase superfamily and act as context-sensitive DNA translocases.57 CHD proteins are distinguished from other SWI2/SNF2 family members by the presence of two tandem chromodomains at their N-terminus, a central catalytic domain, and a C-terminal DNAbinding domain. CHD enzymes have been implicated in transcriptional regulation during diverse biological processes, including differentiation and development.58 Yeast Chd1 is a monomeric remodeler that is capable of remodeling nucleosomes without the involvement of additional subunits. The ATPase activity of Chd1 is stimulated preferentially by nucleosomes rather than naked DNA.59 However, nucleosomes lacking an H4 N-terminal tail fail to activate Chd1 ATPase. The crystal structure of Chd1 revealed that, in the absence of a nucleosome, the 15 ACS Paragon Plus Environment

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double chromodomains block DNA binding to the catalytic domain, conferring an inactive conformation on Chd1 through steric occlusion. Disruption of the interface between the chromodomains and the ATPase domain by mutations promotes DNA binding activity, allowing DNA to stimulate the ATPase activity of mutant Chd1. In addition, these mutant Chd1s are able to translocate nucleosomes without an H4 N-terminal tail, whereas wild-type Chd1 is ineffective in mobilizing the same nucleosome substrate. These observations indicate that the chromodomain-ATPase domain interface functions to discriminate between nucleosome and naked DNA substrates, and that the H4 N-terminal tail likely relieves the chromodomainmediated inactive conformation. The tight cooperation between these intramolecular interactions has also reported for human CHD4—the main subunit of the NuRD (nucleosome remodeling and deacetylase) complex—and human CHD2.60,61 These observations imply that the allosteric regulation of CHD enzymes involving the histone tail and linker DNA that serves to relieve the auto-inhibitory state is evolutionarily conserved among different organisms. CONCLUSIONS AND PERSPECTIVES Establishing and maintaining specific chromatin alterations is crucial for sculpting the proper epigenetic landscape. In particular, robust and precise changes in chromatin architecture that are linked to gene expression are pivotal during dynamic biological processes such as differentiation and adaptation to environmental stress. Distinctive recruitment of chromatin modifiers is unarguably significant for the specificity of chromatin alterations. Given the complexity of target chromatin regions—with their multiple DNA/histone modifications and/or various nucleosome densities—the allosteric regulation of chromatin modifiers, which integrates target region contextual information with catalytic activities, also appears to be critical for precise alteration of chromatin structure. Allosteric pathways are advantageous not only for specificity, but also for selectivity, as evidenced by the case of inhibition of PRC2 enzymatic activity by the active histone modification marks, H3K4me3 and H3K36me2/3. Moreover, weak physical affinities of allosteric effectors for chromatin modifiers, for example in the case of H3K36me2/3-Rpd3S interactions, and their reversibility are beneficial for propagating modifications along large chromatin domains. Therefore, allosteric regulation of the functions of chromatin modifiers is essential for changing the epigenetic landscape under different biological conditions. Recurrent mutations at the PWWP and ADD domains of DNMT3A are implicated in 16 ACS Paragon Plus Environment

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hematological malignancies and developmental disorder such as an overgrowth syndrome with intellectual disability.62,63 In addition, mutations found in non-catalytic sites of several chromatin modifying enzymes are prevalent in various types of cancer.64,65 These exemplify that defects in allosteric regulation of chromatin modifying enzymes are intimately linked to the development of diverse human diseases, bringing attention to clinical point of view. Given its functional significance and clinical relevance, the catalytic activity of chromatin modifiers has been one of the major focuses of drug discovery efforts. However, the well-conserved nature of the catalytic sites of different chromatin-modifying enzymes, which belong to the same family, presents an obstacle for the development of specific targeting strategies. In this context, the allosteric regulatory module, which is specific to a given chromatin modifier, could serve as an alternative target for modulating the activity of chromatin modifiers. A prominent example is the development of an allosteric PRC2 inhibitor targeting the H3K27me3-binding ability of EED as a potent anticancer reagent.66 We envision that rapid advancements in the development of biochemical and structural assays in the field of chromatin biology will expand the list of allosteric regulatory mechanisms and targeted chromatin-modifying enzymes. Accordingly, we expect that, in the near future, modulating allosteric mechanisms that regulate chromatin modifiers will emerge as promising pharmaceutical strategy for controlling the epigenetic landscape associated with diverse physiological and pathological conditions.


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AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. Phone: +82 42 879-8129. *E-mail: [email protected]. Phone: +82 42 350-2632. ORCID Jung-Ae Kim: 0000-0001-5485-4843 Jaehoon Kim: 0000-0003-4035-0438 Funding This work was supported by grants from the National Research Foundation of Korea (NRF2013R1A1A1006638 to J.A.K. and NRF-2018R1A5A1024261 to J.K.); and the KRIBB Research Initiative Program to J.A.K. Notes The authors declare no competing financial interest.


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Biochemistry

TOC GRAPHIC


Biochemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 1 297x420mm (300 x 300 DPI)

ACS Paragon Plus Environment

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Biochemistry

Figure 2 297x420mm (300 x 300 DPI)


Biochemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 3 297x420mm (300 x 300 DPI)


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Biochemistry

Figure 4 297x420mm (300 x 300 DPI)


Biochemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

80x44mm (300 x 300 DPI)


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Allosteric Regulation of Chromatin-Modifying Enzymes - Biochemistry

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