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J. Biol. Chem., Vol. 276, Issue 47, 43499-43502, November 23, 2001

This Article Abstract Full Text (PDF) All Versions of this Article: 276/47/43499    most recent C100549200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Makowski, A. M. Articles by Annunziato, A. T. Search for Related Content PubMed PubMed Citation Articles by Makowski, A. M. Articles by Annunziato, A. T. Social Bookmarking                      What's this?

ACCELERATED PUBLICATION
Effects of Acetylation of Histone H4 at Lysines 8 and 16 on Activity of the Hat1 Histone Acetyltransferase^*

Anita M. Makowski, Robert N. Dutnall^§, and Anthony T. Annunziato^¶

From the  Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467 and the ^§ Division of Biology, University of California, San Diego, La Jolla, California 92093

Received for publication, September 24, 2001, and in revised form, October 1, 2001

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

During nucleosome assembly in vivo, newly synthesized histone H4 is specifically diacetylated on lysines 5 and 12 within the H4 NH₂-terminal tail domain. The highly conserved "K5/K12" deposition pattern of acetylation is thought to be generated by the Hat1 histone acetyltransferase, which in vivo is found in the HAT-B complex. In the following report, the activity and substrate specificity of the human HAT-B complex and of recombinant yeast Hat1p have been examined, using synthetic H4 NH₂-terminal peptides as substrates. As expected, the unacetylated H4 peptide was a good substrate for acetylation by yeast Hat1p and human HAT-B, while the K5/K12-diacetylated peptide was not significantly acetylated. Notably, an H4 peptide previously diacetylated on lysines 8 and 16 was a very poor substrate for acetylation by either yeast Hat1p or human HAT-B. Treating the K8/K16-diacetylated peptide with histone deacetylase prior to the HAT-B reaction raised acetylation at K5/K12 to 70-80% of control levels. These results present strong support for the model of H4-Hat1p interaction proposed by Dutnall et al. (Dutnall, R. N., Tafrov, S. T., Sternglanz, R., and Ramakrishnan, V. (1998) Cell 94, 427-438) and provide evidence for the first time that site-specific acetylation of histones can regulate the acetylation of other substrate sites.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Chromatin replication involves both the transfer of parental histones to new DNA and the assembly of new nucleosomes de novo. To provide the histones required for de novo nucleosome assembly, histone synthesis in somatic cells is for the most part coupled to DNA replication (reviewed in Ref. 1). Newly synthesized H3 and H4 are selectively targeted to nascent DNA by the chromatin assembly factor CAF-1 (2-6), while new H2A, H2B, and H1 enter preexisting chromatin through a process of histone exchange (7, 8).

The core histones (H2A, H2B, H3, and H4) that comprise the histone octamer are subject to reversible posttranslational acetylation on their extended NH₂-terminal "tail" domains. Acetylation occurs on specific, highly conserved lysine residues, e.g. lysines 5, 8, 12, and 16 of H4 and lysines 9, 14, 18, and 23 of H3 (also K27 in some organisms) (reviewed in Ref. 9). A remarkable feature of histone metabolism is that in species as divergent as humans, Drosophila, and Tetrahymena, newly synthesized H4 is specifically diacetylated on lysines 5 and 12 (or lysines 4 and 11 in Tetrahymena, due to a deletion of the typical arginine at position 3) (10, 11). New H4 is acetylated prior to its deposition onto DNA and is subsequently deacetylated following nucleosome assembly (12, 13). Although inhibiting deacetylation prevents the complete maturation of newly replicated chromatin (14, 15), the function of the acetylation of new H4 is unknown (reviewed in Refs. 16-18).

One histone acetyltransferase (or HAT)¹ that may possibly catalyze the acetylation of newly synthesized H4 has been identified. This is the "type B" or HAT-B histone acetyltransferase, which is typically recovered in the cytosol following cellular disruption. HAT-B enzymes have been studied in a number of organisms and have been shown to specifically diacetylate free but not nucleosomal H4 (reviewed in Ref. 18). Moreover, native HAT-B acetyltransferases from humans (19, 20), maize (21), Xenopus (22), and Tetrahymena (23) are capable of generating the complete Lys⁵/Lys¹² acetylation pattern of newly synthesized H4 in vitro (or Lys⁴/Lys¹¹ acetylation for the Tetrahymena enzyme). HAT-B functions as a complex containing the Hat1 catalytic subunit and, in humans, Rbap46 (a small protein that also associates with the retinoblastoma protein, RB) (20). HAT-B enzymes from other species contain orthologues of p46 or of p48 (another RB-binding protein). In yeast, the p46 subunit is termed Hat2p (24, 25).

The crystal structure of the Hat1p acetyltransferase from Saccharomyces cerevisiae (24, 26) has been determined at 2.3-Å resolution (27). Hat1p has a curved shape; acetyl-CoA binds within a depression on the concave surface of the protein, with the acetyl group designating the active site. A model has been proposed for the enzyme-H4 interaction, based on the assumptions that the H4 tail has an extended conformation, that Lys¹² (the lysine more readily acetylated by yeast Hat1p) lies adjacent to the carbonyl group of acetyl-CoA, and that Hat1p itself undergoes no major conformational changes after binding the substrate. By applying these guidelines, it has been proposed that the region of the H4 tail between Lys⁸ and Lys¹⁶ binds along a channel that is long enough to accommodate 6-7 amino acids (27). When Lys¹² is positioned adjacent to the acetyl group of acetyl-CoA, Lys⁸ and Lys¹⁶ are found to lie opposite two acidic patches at the ends of the channel, theoretically engaging in electrostatic interactions that hold the tail in place. Aligning Lys⁵ near the acetyl group of acetyl-CoA also yields a reasonable, though somewhat less favorable, fit. However, modeling Lys⁸ adjacent to acetyl-CoA produces a steric clash with the channel (27, 28).

As noted above, the present model for the binding of the H4 tail to Hat1 predicts that the lysine residues at positions 8 and 16 of H4 play a significant role in stabilizing the Hat1-histone tail interaction. It therefore may be postulated that abrogating the positive charge of Lys⁸ and/or Lys¹⁶ by acetylation should decrease the ability of the H4 tail to bind Hat1 and thus interfere with enzyme activity. In the following report we have tested this prediction directly, by performing HAT assays in vitro using several acetylated H4 NH₂-terminal peptides. We find that the acetylation of Lys⁸ and/or Lys¹⁶ of H4 dramatically reduces the activity of recombinant yeast Hat1p and native human HAT-B in vitro.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Cell Culture; Preparation of HAT-B Extract-- HeLa cells were grown in spinner culture at 37 °C (14). Cytosolic extracts (S100 extract) from HeLa cells were prepared as described previously (19, 29). The HeLa S100 cytosolic extract contains HAT-B as the sole HAT activity, which exclusively acetylates the H4 NH₂ terminus on lysines 5 and 12 (19).

In Vitro Acetylation Assays-- Human HAT-B activity was measured using HeLa cytosolic extracts and an in vitro peptide assay (30), as described previously (19). Synthetic 20-mer peptides (typically 0.1 µg/µl final concentration) corresponding to the first 18 amino-terminal residues (plus a C-terminal Gly-Cys coupling linker) of either unacetylated or variously acetylated NH₂ termini of human histone H4 (19) were incubated in a reaction volume of 80 µl in HB buffer (20 mM Hepes, 5 mM KCl, 1.5 mM MgCl₂, 0.5 mM dithiothreitol, adjusted to pH 7.5 with KOH) containing 40 µl of HeLa S100, an additional 60 mM Hepes (pH 8.0), 5 mM sodium butyrate, and 4-8 µCi/ml [³H]acetyl-CoA (1-3 Ci/mmol; PerkinElmer Life Sciences), for the times indicated in the figure legends; in some cases the reaction volume was doubled. All peptides used in this study were quantitated by mass spectroscopy, and all experiments included parallel reactions using the unacetylated peptide as a positive control. Reactions were stopped by spotting in duplicate onto Whatman P-81 filters, washing with 50 mM NaHCO₃ (pH 9.2), and then with 100% ethanol. Filters were allowed to air dry and then were analyzed by scintillation counting. Control experiments performed in the absence of added peptides, or using a Lys⁵/Lys¹²-diacetylated peptide, confirmed that incorporation was minimal in the absence of proper peptide substrates.

In vitro peptide assays using recombinant Hat1p from S. cerevisiae were performed following a modified procedure of Kleff et al. (26): 40 ng of Hat1p was incubated with synthetic peptides (0.1 µg/µl) in HB buffer containing 75 mM Tris-HCl (diluted from a 1 M stock solution (pH 8.8)), 135 mM NaCl, 5 mM sodium butyrate, and 4 µCi/ml [³H]acetyl-CoA (final reaction volume of 80 µl) for the times indicated. Reactions were stopped and spotted onto Whatman P-81 filters as described above. Recombinant Hat1p was prepared as described previously (27).

Preparation of Histone Deacetylase (HDAC) Extract-- HeLa histone deacetylase extract was prepared as described by Yoshida et al. (31). HeLa cells (250 ml) were washed twice with HDAC buffer (15 mM potassium phosphate (pH 7.5), 5% glycerol, and 0.2 mM EDTA). Cells were allowed to swell on ice for 15 min and were homogenized with a Dounce homogenizer. Nuclei were collected by centrifugation (14,00 × g; 10 min; 4 °C) and resuspended (60 A₂₆₀/ml; A₂₆₀ measured in SDS) in HDAC buffer plus 1 M (NH₄)₂SO₄. After a second homogenization, samples were sonicated for 10 s and pelleted as described above. The supernatant, containing histone deacetylase activity, was brought to a final concentration of 3.5 M (NH₄)₂SO₄, kept on ice for 30 min, and centrifuged. The pellet was resuspended in 500 µl of HDAC buffer and dialyzed overnight to 1 liter of HDAC buffer. Samples were then stored at 70 °C. HDAC activity was monitored using [³H]acetate-labeled acetylated histones as substrates.

Treatment of Peptides with Histone Deacetylase-- Following the procedure of Inoue and Fujimoto (32), 8 µg of peptide were added to 37 µl of HDAC extract and incubated for 1 h at 37 °C. Samples were boiled for 5 min and cooled. HDAC extracts treated in this manner contained no contaminating HAT activity, as determined by HAT assay. HDAC-treated peptides were then used in subsequent HAT-B reactions, containing 45 µl of deacetylated peptide/HDAC extract, 40 µl of HeLa S100 cytosolic extract, 60 mM Hepes (pH 8.0), 20 mM sodium butyrate, and 0.32 µCi of [³H]acetyl-CoA, adjusted to a final reaction volume of 100 µl with HB buffer.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Histone H4 NH₂-terminal peptides were synthesized in various isoforms, representing the following acetylation states: unacetylated; monoacetylated at either Lys⁵, Lys⁸, Lys¹², or Lys¹⁶ (termed Mono-5, Mono-8, Mono-12, and Mono-16, respectively); and diacetylated at either Lys⁵/Lys¹², or Lys⁸/Lys¹⁶ (Di-5/12 and Di-8/16). The peptides were then used to examine the activity of recombinant yeast Hat1p, as measured by the transfer of radiolabeled acetate from [³H]acetyl-CoA. All acetylation reactions were performed in the presence of sodium butyrate, to inhibit possible deacetylation during incubation. The results are presented in Fig. 1.

View larger version (18K): [in this window] [in a new window]   Fig. 1.   Acetylation of H4 NH2-terminal tail peptides by the yeast HAT-B catalytic subunit, Hat1p. Unacetylated (); monoacetylated at lysine 5, 8, 12, or 16 (, , , or ); or diacetylated at lysines 5 and 12 (×) or at lysines 8 and 16 () human H4 NH2-terminal peptides were incubated in vitro for the times indicated with Hat1p and [3H]acetyl-CoA.

As predicted, an H4 peptide already acetylated on lysines 5 and 12 (the sites acetylated by Hat1 enzymes) was an extremely poor substrate (Fig. 1). The depressed acetylation of the Di-5/12 peptide also verifies that no significant deacetylation is occurring under our experimental conditions. In contrast, both the unacetylated peptide and the peptide previously acetylated on Lys⁵ were readily acetylated by Hat1p. Labeling of the Mono-5 peptide was reduced relative to the unacetylated substrate (Figs. 1 and 2). This is as expected, since only one substrate lysine is available for radiolabeling; however, other factors may also be involved (see "Discussion"). Notably, the Mono-12 peptide was acetylated poorly (Figs. 1 and 2), consistent with the great preference of native and recombinant yeast Hat1p for Lys¹² over Lys⁵ (24, 26).

View larger version (17K): [in this window] [in a new window]   Fig. 2.   Prior acetylation of H4 NH2-terminal peptides affects further acetylation at Lys5/Lys12 by yeast Hat1p. Unacetylated (Unacet.), monoacetylated at lysines 5, 8, 12, or 16 (K5, K8, K12, K16), or diacetylated (K8/K16 or K5/K12), H4 NH2-terminal peptides were incubated for 60 min with yeast Hat1p and [3H]acetyl-CoA. Results are expressed as a percentage of incorporation into the unacetylated H4 peptide, which was determined in all experiments.

The effect of prior acetylation Lys⁸ and Lys¹⁶ (which are not substrate lysines for Hat1p) on Hat1p activity was then examined (Fig. 1). As predicted from the proposed interaction of the H4 tail with Hat1p (27), acetylation at either Lys⁸ or Lys¹⁶ significantly reduced the ability of Hat1p to acetylate its substrate lysines, with acetylation at Lys¹⁶ having a somewhat greater effect. Strikingly, the Lys⁸/Lys¹⁶-diacetylated peptide was almost refractory to acetylation by Hat1p, yielding results close to those obtained with the 5/12-diacetylated peptide, in which the substrate lysines are already acetylated. A summary of the results from several independent experiments are presented in Fig. 2, in which incorporation of radiolabeled acetate into each of the substrates is presented relative to that of the unacetylated peptide, which was always tested as a positive control. The combined data demonstrate that lysines 8 and 16 of H4 are critical to Hat1p activity (at least in vitro).

The experiments were then repeated using the human Hat1 enzyme, which in vivo resides in the HAT-B complex (19, 20). One of the hallmark features of HAT-B enzymes is their fractionation into the cytosol following cell disruption. We have previously shown that HAT-B is the sole HAT activity present in a cytosolic extract prepared from HeLa cells ("S100" extract) and that human HAT-B acetylates H4 exclusively in the Lys⁵/Lys¹² deposition pattern (19). Moreover, HAT-B in the S100 comprises a native complex of ~100 kDA (19), which contains Hat1 and p46 (20). It is therefore possible to study HAT-B activity using the S100 extract as a native enzyme source (19).

Unacetylated, as well as Mono-8, Mono-16, Di-5/12, and Di-8/16 acetylated peptides, were tested for their ability to be acetylated by human HAT-B; also tested was an H4 NH₂-terminal peptide with a deletion of Lys¹⁶ (Fig. 3). Control experiments verified by immunoprecipitation of the acetylated peptides with site-specific anti-acetylated H4 antibodies (19) that HAT-B was acetylating lysines 5 and 12 of the H4 tail (data not presented), consistent with our previous description of human HAT-B activity (19).

View larger version (15K): [in this window] [in a new window]   Fig. 3.   Substrate preference of HeLa HAT-B. Unacetylated (Unacet.), monoacetylated at lysines 8 or 16 (K8 or K16), or diacetylated (K8/K16 or K5/K12) H4 NH2-terminal peptides were incubated for 10 min with a cell extract containing human HAT-B and [3H]acetyl-CoA. Also analyzed was an H4 NH2-terminal peptide with a deletion of Lys16 (()16). Results are expressed as a percentage of incorporation into the unacetylated H4 peptide.

Deleting or acetylating Lys¹⁶ reduced the ability of HAT-B to acetylate the H4 peptide by ~50%, and acetylating Lys⁸ had a slightly greater effect (Fig. 3). The more pronounced effect of Lys¹⁶ acetylation on the activity of recombinant Hat1p (Figs. 1 and 2), relative to human HAT-B (Fig. 3), may be due to the presence of the p46 subunit in the human enzyme; it has been demonstrated that the interaction of the H4 tail with yeast Hat1p is stabilized by Hat2p (24). Notably, as seen earlier with yeast Hat1p, the simultaneous acetylation of Lys⁸ and Lys¹⁶ severely reduced the acetylation of the H4 tail by the human enzyme (Fig. 3). Competition experiments further established that the Lys⁸/Lys¹⁶-diacetylated peptide did not inhibit HAT-B activity, even when present in 10-fold excess over the unacetylated peptide (data not presented). Thus the Lys⁸/Lys¹⁶ peptide is itself a poor Hat1p/HAT-B substrate.

Additional experiments were then performed to ensure that acetylation per se was regulating HAT-B activity. For these experiments, a preparation of HDAC was obtained from isolated HeLa cell nuclei (see "Experimental Procedures"). Unacetylated and Lys⁸/Lys¹⁶-diacetylated H4 peptides were then pretreated with HDAC prior to using the peptides in HAT-B assays. Control experiments verified that no contaminating HAT activities from the HDAC extract were present during the subsequent HAT-B reactions.

Pretreating the Lys⁸/Lys¹⁶-diacetylated peptide with HDAC enabled HAT-B to acetylate the peptide at lysines 5 and 12, to 75-80% of control levels; buffer alone or BSA had no effect (Fig. 4, A and B). Moreover, HDAC activity was essential during pretreatment; adding sodium butyrate to the HDAC reaction to inhibit deacetylases prevented the restoration of full HAT-B activity in the subsequent HAT-B reaction (Fig. 4B). Thus, acetylation at Lys⁸/Lys¹⁶ is responsible for the reduction in HAT-B activity.

View larger version (12K): [in this window] [in a new window]   Fig. 4.   Acetylation of a diacetylated-Lys8/Lys16 peptide by human HAT-B is increased after treatment with histone deacetylase. A, unacetylated (Un) or Lys8/Lys16-diacetylated (K8/K16) H4 NH2-terminal peptides were incubated in the presence or absence of a cell extract containing HDAC activity. After the deacetylation reaction, peptides were incubated for 10 min with human HAT-B extract and [3H]acetyl-CoA; B, unacetylated (Un) or diacetylated (K8/K16) H4 NH2-terminal peptides were incubated in the presence (+HDAC) or absence (+BSA) of a cell extract containing human histone deacetylase activity; 25 mM sodium butyrate (+NaBut) was added to the Lys8/Lys16 HDAC reaction to inhibit HDAC activity. After the reactions, peptides were incubated for 10 min with human HAT-B extract and [3H]acetyl-CoA. For A and B, results are expressed as a percentage of incorporation into the unacetylated H4 peptide.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The acetylation of specific, nonsubstrate lysine residues (i.e. Lys⁸ and Lys¹⁶) of the histone H4 NH₂ terminus reduces the acetylation of lysines 5 and 12 by both yeast and human Hat1 enzymes in vitro. Our results provide strong support for the model of H4-Hat1p interaction proposed by Dutnall et al. (27, 28), in which Lys⁸ and Lys¹⁶ are postulated to interact electrostatically with acidic domains within the Hat1p active site. In addition, this is the first demonstration that the activity of any histone acetyltransferase can potentially be regulated by the prior acetylation of nonsubstrate lysine residues within an individual histone tail.

Yeast Hat1p exhibits a strong preference for acetylating Lys¹² of H4 over Lys⁵ (24, 26). In light of this, it might be expected that acetylation of the Mono-5 peptide (with Lys¹² available for modification) would more closely approach that of the unacetylated peptide (Fig. 2). The presence of acetylation on Lys⁵ may therefore lower the ability of the H4 tail to interact with HAT-B. Notably, it has been shown by Loidl and colleagues (21) that maize HAT-B is incapable of using a native mixture of monoacetylated H4 isoforms as a substrate, although in this case the specific lysines inhibiting acetylation were not identified. Thus in that study a significant percentage of input H4 was very likely acetylated on Lys⁵ or Lys¹².

It is now becoming clear that histone acetyltransferases may be controlled (either positively or negatively) by posttranslational modifications on residues that neighbor HAT-specific target lysines. For example, it has recently been shown that the Gcn5 histone acetyltransferase strongly prefers phosphorylated over unphosphorylated H3 as a substrate and that prior phosphorylation at serine 10 of H3 can potentiate subsequent acetylation of lysine 14 (33, 34). Moreover, the methylation of H3 at lysine 9 inhibits the phosphorylation of H3 at serine 10 (35), and it has been proposed that histone methylation can help to regulate acetylation (and vice versa), at least in some instances (36). While our experiments have focused on the activity of Hat1 in vitro, peptide assays have previously been shown to be excellent predictors of the interactions between histone modifications in vivo, as seen with the enhancement of H3 acetylation by phosphorylation (33, 34) and the inhibition of H3 phosphorylation by prior methylation (35). The positive or negative interaction of histone modifications thus appears to be a general regulatory mechanism of histone metabolism, as detailed in the "histone code" hypothesis proposed by Strahl and Allis (37), in which histone modifications act in concert to regulate gene activity.

Hat1 is most likely involved in the acetylation of newly synthesized H4, which is not expected to be pre-acetylated at lysines 8 and/or 16. Nevertheless, our results have relevance beyond supporting the proposed model of H4-Hat1 interaction. For example, in human cells a nuclear CAC complex (comprising the chromatin assembly factor CAF-1 and histones H3 and H4) has been described, in which a fraction of H4 is acetylated at Lys⁸, as well as at Lys⁵ and Lys¹² (38). The CAC complex thus appears to represent a chromatin-bound intermediate in the deposition of new H4 onto chromatin, isolated prior to the deacetylation of nascent H4. Our results now suggest that the acetylation of new H4 at Lys⁸ should follow the acetylation of Lys⁵ and Lys¹² by HAT-B, since prior acetylation of Lys⁸ could inhibit the activity of human HAT-B.

Although Hat1 is typically recovered from cytosolic extracts, there is evidence that the great majority of the human Hat1 is nuclear in vivo (20). Nuclear as well as cytoplasmic HAT-B type enzymes have also been described in Tetrahymena cells (23) and maize embryos (39). Interestingly, Hat1 in Xenopus oocytes has been demonstrated to shuttle between nuclear and cytoplasmic compartments (22), and in yeast, Hat1p is found in two separate complexes, at least one of which is nuclear (25). It has been shown that the activity of HAT enzymes can be modulated by their association with other proteins within HAT-containing complexes (reviewed in Ref. 40), and it remains to be seen whether the Hat1 catalytic subunit can in some circumstances associate with proteins that expand its specificity to include nucleosomal histones in vivo. If so, pre-existing acetylation patterns could also help to regulate nuclear Hat1 complexes that engage chromatin-bound substrates.

	FOOTNOTES

^* This work was supported by National Institutes of Health Grant GM 35837 (to A. T. A.) and by a Boston College Research Incentive grant.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This communication is dedicated to the memory of Dr. Alan Wolffe.

^¶ To whom correspondence should be addressed: Dept. of Biology, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467. Tel.: 617-552-3812; Fax: 617-552-2011; E-mail: anthony.annunziato@bc.edu.

Published, JBC Papers in Press, October 3, 2001, DOI 10.1074/jbc.C100549200

	ABBREVIATIONS

The abbreviations used are: HAT, histone acetyltransferase; HDAC, histone deacetylase; RB, retinoblastoma.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 276/47/43499    most recent C100549200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Makowski, A. M. Articles by Annunziato, A. T. Search for Related Content PubMed PubMed Citation Articles by Makowski, A. M. Articles by Annunziato, A. T. Social Bookmarking                      What's this?