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<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="k4gLuYQ3LLqfDmUAPusote67ihY8brQVBR0Q7OjplmdJxN0qsN5qXmCLQlGk42of">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="k4gLuYQ3LLqfDmUAPusote67ihY8brQVBR0Q7OjplmdJxN0qsN5qXmCLQlGk42of">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="k4gLuYQ3LLqfDmUAPusote67ihY8brQVBR0Q7OjplmdJxN0qsN5qXmCLQlGk42of">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="k4gLuYQ3LLqfDmUAPusote67ihY8brQVBR0Q7OjplmdJxN0qsN5qXmCLQlGk42of">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="k4gLuYQ3LLqfDmUAPusote67ihY8brQVBR0Q7OjplmdJxN0qsN5qXmCLQlGk42of">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="21804188">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1172/JCI43428"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=6619&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=21804188&amp;db=pubmed&amp;nlmid=7802877"
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American Society for Clinical Investigation
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/21804188/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=21804188&amp;db=pubmed&amp;nlmid=7802877"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
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Free PMC article
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<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/21804188/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/21804188/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="21804188" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F21804188%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="k4gLuYQ3LLqfDmUAPusote67ihY8brQVBR0Q7OjplmdJxN0qsN5qXmCLQlGk42of"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
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Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.
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<img class="figure-thumb" itemprop="thumbnail"
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<p> Figure 1. Phenotype and genetic studies in… </p>
</strong>
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<p> Figure 1. Phenotype and genetic studies in the patient with MYST4 haploinsufficiency at age 6… </p>
</strong>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. Phenotype and genetic studies in the patient with MYST4 haploinsufficiency at age 6 years.
</strong>
<div class="figure-caption-contents">(<b>A</b>) Note the mild funnel chest and the genua valga and facial dysmorphism (<b>B</b><b>D</b>) with blepharophimosis, ptosis, high arched eyebrows, low-set ears, smooth philtrum, and retrognathia and a high arched palate. Ptosis was surgically treated at age 5 and 6 years. (<b>E</b>) Representative metaphase spread of the patient using the BAC clone RP11-668A2 (red, arrows), with hybridization signals localized on both derivative chromosomes, spanning the breakpoint region. Original magnification, ×1,000. (<b>F</b>) Breakpoint sequencing after long-range PCR indicating the breakpoint (red dotted line) disrupting the <i>MYST4</i> gene in intron 3. Chr., chromosome. (<b>G</b>) Relative mRNA expression levels of the haploinsufficient <i>MYST4</i> gene and the <i>TUBGCP3</i> gene 3 of the breakpoint region in the peripheral blood of the patient (P) and 3 healthy age-matched controls (C1C3). Note the significant decrease of <i>MYST4</i> expression levels in the patient (*<i>P</i> &lt; 0.001, <i>t</i> test) but unchanged relative expression levels of <i>TUBGCP3</i> (**<i>P</i> &lt; 0.8, <i>t</i> test). RQ, relative quantification.</div>
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
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<p> Figure 2. Structure and histone acetylation of… </p>
</strong>
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<strong class="figure-label">
<p> Figure 2. Structure and histone acetylation of MYST4. </p>
</strong>
<div class="figure-caption-contents"><p> ( <b> A </b> ) Three <i> MYST4 </i> isoforms have… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2. Structure and histone acetylation of MYST4.
</strong>
<div class="figure-caption-contents">(<b>A</b>) Three <i>MYST4</i> isoforms have been identified (<i>MORF</i>, <i>MORF</i>α, and <i>MORF</i>β) to differ in the negative regulator for HAT domain (NRHD) coded by exon 8. The red line indicates the site of translocation (exon 3/4 boundary at amino acid position 207) with respect to protein structure. Note histones H1- and H5-like domain (H15), C4HC3 PHD-zinc fingers (PHD), and the N-terminal part of Enok, MOZ, or MORF (NEMM). Numbers represent amino acids. NH2, N-terminal end of the protein; 2x PHD, 2-times PHD domain; C2HC, zinc finger motif domain. (<b>B</b>) Time course of histone acetylation activity in a cell line of the patient compared with that of controls (Ctrls). (<b>C</b>) Significant decrease of global H3 (*<i>P</i> &lt; 0.05, <i>t</i> test) but normal H4 acetylation in the patient (<i>t</i> test).</div>
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alt="Figure 3" />
</a>
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<strong class="figure-label">
<p> Figure 3. Effect of different <i> MYST4 </i> siRNAs… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3. Effect of different <i> MYST4 </i> siRNAs on H3 and H4 acetylation. </p>
</strong>
<div class="figure-caption-contents"><p> ( <b> A </b> )… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 3. Effect of different <i>MYST4</i> siRNAs on H3 and H4 acetylation.
</strong>
<div class="figure-caption-contents">(<b>A</b>) Results of quantitative RT-PCR revealed significantly reduced <i>MYST4</i> mRNA expression levels in both cell lines (*<i>P</i> &lt; 0.05, <i>t</i> test), HEK293 and HeLa, after exposure to 3 different <i>MYST4</i> siRNAs (1, HSS118879; 2, HSS118880; 3, HSS118881). (<b>B</b>) Significant decrease of global H3 but (<b>C</b>) normal H4 acetylation was confirmed in HEK293 and HeLa cell lines (*<i>P</i> &lt; 0.05, <i>t</i> test; **<i>P</i> &lt; 0.00001, <i>t</i> test). Note the correlation between MYST4 depletion levels and loss of H3 acetylation (<i>P</i> &lt; 0.02793, rank correlation coefficient) but not H4 acetylation (<i>P</i> &lt; 0.9349, rank correlation coefficient). Based on these results the siRNA HSS118880 was used for further analysis. Numbers in the bars are the relative quantification.</div>
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
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<p> Figure 4. <i> Qkf <sup> gt/gt </sup> </i> mutant mice deficient… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4. <i> Qkf <sup> gt/gt </sup> </i> mutant mice deficient in Myst4. </p>
</strong>
<div class="figure-caption-contents"><i> Qkf <sup> gt/gt </sup> </i> mutant mice deficient in MYST4…</div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 4. <i>Qkf<sup>gt/gt</sup></i> mutant mice deficient in Myst4.
</strong>
<div class="figure-caption-contents"><i>Qkf<sup>gt/gt</sup></i> mutant mice deficient in MYST4 exhibit facial and skeletal abnormalities. (<b>A</b><b>C</b>) External appearance of <i>Qkf<sup>gt/gt</sup></i> mutant mice versus that of controls at 7 weeks of age. (<b>D</b> and <b>E</b>) Close-up images of the eyes. (<b>F</b> and <b>G</b>) Skeletal preparation of the lower jaw. (<b>H</b><b>K</b>) β-Galactosidase reporter activity (blue) representing the high <i>Qkf</i> gene expression domains (<b>H</b> and <b>I</b>) in cartilage primordia of the developing skeletal system at E15.5, (<b>J</b>) primordia of the cerebral cortex and skeletal elements at E12.5, and (<b>K</b>) the adult parietal cortex (Ctx) and hippocampus (Hi). (<b>L</b>) Endogenous <i>Qkf</i> mRNA detected by in situ hybridization in skeletal primordia of the E15.5 hind limb (precipitated silver grains corresponding to <i>Qkf</i> mRNA appear white in dark-field image). Arrows indicate coronoid process in <b>F</b> and <b>G</b>, strongly Qkfβ-galactosidasepositive cells in <b>H</b> and <b>I</b>, telencephalon and mandibular process in <b>J</b> and <b>K</b>, and endogenous <i>Qkf</i> mRNA expressing cells in skeletal primordia in <b>L</b>. (<b>M</b>) In mice, the tibia and the fibula normally fuse in their distal third. (<b>M</b>) The <i>Qkf<sup>gt/gt</sup></i> mutant mice lack the fusion of the tibia and fibula (<b>N</b>) normally observed in wild-type mice. Scale bar: 190 μm (<b>H</b>); 65 μm (<b>I</b>); 160 μm (<b>J</b>); 790 μm (<b>K</b>); 910 μm (<b>L</b>); and 3.6 mm (<b>M</b> and <b>N</b>).</div>
</figcaption>
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
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<p> Figure 5. Myst4 deficiency alters growth plate… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5. Myst4 deficiency alters growth plate in mice. </p>
</strong>
<div class="figure-caption-contents"><p> ( <b> A </b> , <b> C </b> , <b> E… </b> </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 5. Myst4 deficiency alters growth plate in mice.
</strong>
<div class="figure-caption-contents">(<b>A</b>, <b>C</b>, <b>E</b>, and <b>G</b>) Wild-type and (<b>B</b>, <b>D</b>, <b>F</b>, and <b>H</b>) <i>Qkfgt/gt</i> mutant growth plates. (<b>A</b>, <b>B</b>, <b>E</b>, and <b>F</b>) Toluidine blue/fast green, (<b>C</b> and <b>D</b>) safranin O/fast green, and (<b>G</b> and <b>H</b>) Massons trichromestained sections of (<b>A</b> and <b>B</b>) E15.5 distal femur, (<b>C</b> and <b>D</b>) E18.5 proximal and (<b>E</b><b>H</b>) distal femur. (<b>A</b> and <b>B</b>) Disorganization in the <i>Qkfgt/gt</i> mutant hypertrophic (H) region was visible at E15.5 and (<b>c</b><b>f</b>) more pronounced at E18.5 and enlarged in <b>G</b> and <b>H</b>. Arrows delineate the border of the hypertrophic zone. Note the poor demarcation between the <i>Qkfgt/gt</i> proliferative (P), hypertrophic, and chondrolytic (C) regions, as compared with those of wild-type regions, particularly in <b>F</b> versus <b>E</b> (indicated with white lines), the reduced height of the hypertrophic region (167 μm in <b>E</b> versus mean height of 136 μm in <b>F</b>; <i>P</i> value &lt; 0.05), and the aberrant columnar structure in the hypertrophic region (<b>H</b> versus <b>g</b>). Scale bar: 55 μm (<b>A</b> and <b>B</b>); 180 μm (<b>C</b> and <b>D</b>); 95 μm (<b>E</b> and <b>F</b>); and 90 μm (<b>G</b> and <b>H</b>).</div>
</figcaption>
</figure>
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itemprop="contentUrl"
aria-describedby="figure-caption-5"
role="button"
data-image-width="466"
data-image-height="504"
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data-pmc-id="PMC3163944"
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id="article-image-5"
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<p> Figure 6. Biochemical characterization of MEK, ERK,… </p>
</strong>
</div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 6. Biochemical characterization of MEK, ERK, and AKT phosphorylation levels. </p>
</strong>
<div class="figure-caption-contents"><p> ( <b> A </b> ) Increased… </p></div>
</div>
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 6. Biochemical characterization of MEK, ERK, and AKT phosphorylation levels.
</strong>
<div class="figure-caption-contents">(<b>A</b>) Increased MAPK signaling activity of the patient (P1) containing the MYST4 mutation compared with 3 control samples (C1C3). The patient cell line transiently transfected with an MYST4 wild-type construct (R) demonstrated a normalization of the phosphorylation levels. Cells were analyzed for the phosphorylation level of MEK/pMEK1/2 (MAP2K/pMAP2K1/2), ERK/pERK1/2, and AKT/pAKT. Total amounts of MEK, ERK, and AKT and actin in cell lysates are shown, and the specificity of the antibody is specified below each panel. (<b>B</b>) After normalization to actin, densitometric analysis confirmed significantly increased ratios of all 3 measured parameters (*<i>P</i> &lt; 0.05, <i>t</i> test) and normalization to wild-type ratios after rescue of MYST4 expression levels.</div>
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itemprop="contentUrl"
aria-describedby="figure-caption-6"
role="button"
data-image-width="605"
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data-image-alt="Figure 7"
data-pmc-id="PMC3163944"
data-figure-id="F7">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-6"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bad/3163944/f5a81507665f/JCI43428.f7.gif"
alt="Figure 7" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="605">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="602">
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<div class="caption-wrap">
<strong class="figure-label">
<p> Figure 7. The MAPK signaling pathway. </p>
</strong>
<div class="figure-caption-contents"><p> Overview… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 7. The MAPK signaling pathway. </p>
</strong>
<div class="figure-caption-contents"><p> Overview of genes with ChIP-CHIP binding sites and differential… </p></div>
</div>
<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 7. The MAPK signaling pathway.
</strong>
<div class="figure-caption-contents">Overview of genes with ChIP-CHIP binding sites and differential expression. Three out of the four major branches of the MAPK signaling pathway are shown: ERK1/2 (MAP2K1/2), c-Jun, and p38 (modified from KEGG pathway map 04010; <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.genome.jp/kegg/">
http://www.genome.jp/kegg/</ext-link>). Mutations affecting the ERK1/2 (MAP2K1/2) branch are identified in approximately 70% of patients with Noonan syndrome (genes marked with orange stars). Note that genes with significant ChIP-on-CHIP bindings sites (Supplemental Table 23) are marked in yellow; additional significantly differentially expressed genes in the human cell lines are marked with red boxes.</div>
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