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R E S E A R C H H I G H L I G H T S

AGING

Blame it on acetylationDuring aging, the brain gene expression pro-

gram changes, and people often suffer declines

in learning and memory. A study in mice sug-

gests that altered patterns of histone acetyla-

tion may underlie this age-related decline.

Previous studies have shown that chromatin

plasticity and histone modifications, especially

acetylation, are involved in long-term memory

and regulation of gene expression. Shahaf

Peleg et al. (Science328, 753756) exam-

ined these processes in mice as they aged

and found impaired acetylation of histone

H4 Lys12 (H4K12).

The researchers assessed the entire hip-

pocampal transcriptome of aged mice right after

subjecting them to fear conditioning training

a test for learning and memory. Compared to

younger mice, these animals failed to upregulategenes encoding proteins linked to learning and

memory formation, such as formin-2an actin

nucleator expressed in the brain. The research-

ers traced the failure to upregulate these genes

to defects in H4K12 acetylation, which specifi-

cally affected transcriptional elongation.

Treatment with a histone deacetylase

inhibitor rescued the acetylation of H4K12

in coding regions of learning-regulated genes

in aged mice. The genes were upregulated

and memory function reinstated during the

learning test. CP

REPRODUCTION

Steroids fry brain, fry testesA new study in mice might give pause to

adolescent boys contemplating using ste-

roids. Synthetic derivatives of testosterone

can alter a hormone-controlling circuit in the

brain, leading to shrunken testes, accord-

ing to a study in adolescent male mice

(J. Neurosci.30, 64976506).

Carlos Penatti et al. treated mice with

17-methyltestosterone and looked at the

response of neurons in the hypothalamusthat release gonadotropin-releasing hormone

(GnRH). GnRH prompts the production of

hormones that regulate key reproductive pro-

cesses, such as spermatogenesis.

The steroid-treated mice had reduced

action potentials in GnRH neurons, reduced

levels of reproductive hormones and reduced

testes mass. The steroid does not seem to

affect GnRH neurons directlyinstead, it

affects a nearby part of the brain, the medial

preoptic area (mPOA). Steroid administration

increased the action potential frequency of

neurons in the mPOA, which, in turn, damp-

ened the firing rate of GnRH neurons.

The findings jibe with observations that ste-

roids can delay the onset of puberty in mice

and can affect libido, testes health and sperm

production in people. CS

NEUROSCIENCE

Trimming synapsesThe neurons of individuals with fragile X syn-

drome contain an overabundance of synapses.

A study in mice suggests that a failure in syn-

aptic pruning may underlie this problem of

excess (Neuron 66, 191197).

The transcription factor myocyte enhancer

factor-2 (MEF2) drives synaptic elimination in

response to neuron firing. When Brad Pfeiffer

et al. expressed a constitutively active form of

MEF2 in hippocampal slice cultures from nor-

mal mice, they observed a decrease in spine

number and synaptic activity. These changes

were not observed when MEF2 was expressedin slice cultures from mice deficient in FMRP,

the protein behind fragile X syndrome. The

researchers found that re-expressing FMRP at

the synapses of these neurons could drive syn-

aptic elimination in response to MEF2.

FMRP and MEF2 did not seem to bind

each other to exert their effects. Instead, the

researchers suggest that these two factors may

operate in a common pathwaywith MEF2

inducing transcription in the nucleus and FMRP

binding these transcripts once they arrive at

the synapseto regulate synaptic elimination.

Future work looking at the downstream targets

of these factors could provide further insight

into fragile X syndrome. EC

IMMUNITY

Balance in the bowelOne approach to treating inflammatory bowel

disease, now in clinical trials, is to block the

activity of OX40a molecule that ramps up

the immune response by acting as a co-stim-

ulatory receptor on T cells. New findings in

mice sound a note of caution for this approach.

It seems that blocking OX40 interferes with

the function of regulatory T cells, cells that

suppress activation of the immune system

and dampen inflammation (J. Exp. Med. 207,

699709).

Colitis results from an imbalance between

effector and regulatory T cells (Treg cells) in

the gut. In mice, blocking OX40 can help rein

in effector T cells and has shown therapeutic

effects in animal models of colitis. To furtherexplore how OX40 affects the balance between

immune cells, Thibault Griseri et al.turned

to mice unable to form T and B cells (RAG-

deficient mice). They transferred colitis-induc-

ing T cells into these mice along with Treg cells.

Concurrently transferring OX40-expressing

Treg cells prevented development of disease,

whereas transfer of Tregcells deficient in OX40

resulted in severe inflammation and colitis.

Unlike OX40-expressing Treg cells, OX40-

deficient Tregcells failed to accumulate in the

colon or lymphoid organs of RAG-deficient

MICROBIOLOGY

Leaping Listeria

The savvy bacterium Listeria monocytogenesuses a

one-two punch to invade the intestinal epithelium,

report Mickey Pentecost etal.(PLoSPathog. 6,

e1000900).

At the tips of intestinal villi, extrusion ofdead cells causes the surrounding live cells to

form multicellular junctions, where normally

basolateral proteins, such as E-cadherin, are

transiently exposed to the lumen.

L. monocytogenescapitalizes on this quirk and

uses the invasin protein InlA to bind E-cadherin

and enter the cell.

In their new study, Pentecost etal.find that L. monocytogenesdeploys a second invasin,

InlB, to trigger signaling through another basolateral protein, c-Met. This signaling induces

endocytosis of E-cadherin, accelerating L. monocytogenesinvasion at the multicellular

junction. The researchers propose that other gastrointestinal pathogens may also take

advantage of this unique entry site.

In a separate study on L. monocytogenes, David Ribet et al.find that the microbe impairs

an essential post-translational modification, SUMOylation (Nature464, 11921195).

Theresearchers identified a specific bacterial protein that prompts the degradation of an enzyme

in the SUMOylation machinery, thereby weakening the host immune response.KG

L. monocytogenes(green) after invading an

intestinal villus tip (red).

P L o S P a t h o g e n s

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R E S E A R C H H I G H L I G H T S

mice during the early stages of disease. The

researchers traced this defect to increased

apoptosis and reduced activation of OX40-

expressing Treg cells. They conclude that OX40

may act as a survival signal in Treg cells. CP

ATHEROSCLEROSIS

Insulin controls adhesionInsulin signaling in the vasculature shields

mice from atherosclerosis, according to new

research (Cell Metab. 11, 379389).

Studies on whether insulin prevents or

promotes atherosclerosis are contradictory.

To shed light on the conflict, Christian Rask-

Madsen et al.deleted the gene encoding

the insulin receptor in endothelial cells in

apolipoprotein E (apoE)-deficient mice, a model

of atherosclerosis. The double-knockout mice

had larger and more complex aortic atheroscle-

rotic lesions than did apoE-deficient mice.The researchers next examined recruit-

ment and accumulation of

inflammatory cells in the

vasculature, a key step in

the development of athero-

sclerosis. They found that

insulin seems to downregu-

late VCAM-1, a molecule on

the endothelium that binds

leukocytes. Endothelial

cells from the double-

knockout mice, for instance,

showed high expression of

VCAM-1, compared to cells

from apoE-deficient mice.

Treating wild-type endothe-

lial cells with insulin quashed

VCAM-1 protein expression.

In a system already prone to atherosclero-

sis, it seems that insulin signaling can inhibit

lesion formation by downregulating VCAM-1

expression and leukocyte adhesion. The find-

ings provide insight into how impaired insulin

signaling in the endothelium in conditions

such as type 2 diabetes should be managed to

decrease the risk of atherosclerosis. AK

Cholesterol microcontrolTwo new studies identify a noncoding RNA as a

key regulator of cholesterol homeostasis.

S. Hani Najafi-Shoushtari et al.found a

conserved microRNA, miR-33, in the intronic

sequences of two genes that encode sterol-

regulatory element-binding protein (SREBP)

transcription factors, proteins which promote

the synthesis and uptake of cholesterol and lip-

ids (Sciencedoi:10.1126/science.1189123).

Katey Rayner et al.pulled the same miRNA out

of a screen for miRNAs that respond to changes

in cholesterol levels (Sciencedoi:10.1126/

science.1189862).

Expression of miR-33 mirrored that of its

host SREBP genes in both mouse and human

cells and tissues. Among other targets, miR-33

quashes expression of ATP-binding cassette

A1 (ABCA1)a transporter protein that medi-

ates the formation of high-density lipoprotein

(HDL), the 'good' cholesterol, and aids its efflux

from cells. Overexpression of miR-33 in mice

decreased ABCA1 protein expression, whereas

inhibition of miR-33 increased ABCA1 expres-

sion and raised circulating HDL levels.

The findings suggest that manipulation of

miR-33 expression has the therapeutic poten-

tial to increase expression of ABCA1 and

thereby raise HDL levels. AK

GENOMICS

The whole thing, lots of itA clinical annotation of the complete genome

sequence of a healthy person has revealed dis-

ease risks and drug response predictions (Lancet

375, 15251535, 2010). But the work under-

scores the bioinformatic challenges remaining

before scientists can confidently apply genetic

information to personalized medicine.

Euan Ashley et al. scoured the DNA of a

40-year-old man for 2.6 million single nucle-

otide polymorphisms and more than 750 copy

number variants. Incorporating family history,

clinical measurements and known disease

associations, they showed that this individual

was at an elevated risk of developing sudden

cardiac arrest, diabetes and some cancersand

that he might benefit from cholesterol-lowering

statins.

The study emerges on the heels of two oth-

ers comparing whole-genome sequences from

people with rare genetic disorders to genetic

information from unaffected relatives. Jared

Roach et al. sequenced the DNA of a family

of four, including two adult children who suf-

fer from Miller's syndrome and primary cili-

ary dyskinesia, and pinpointed the four genes

responsible for the two diseases (Science328,636639, 2010).

James Lupski, who is afflicted with a reces-

sive form of Charcot-Marie-Tooth disease, ana-

lyzed his own genome. He and his colleagues

homed in on the mutation causing the condition

in the Baylor College of Medicine geneticist and

some of his family members (New Engl. J. Med.

362, 11811191, 2010). ED

New from NPG

Mutations of optineurin in amyotrophic

lateral sclerosis.

Maruyama, H. et al. Nature465, 223226.

A gene previously implicated in a form of

glaucoma is now pinned to amyotrophiclateral sclerosis. Mutations in the

gene affect signaling through NF-B,

suggesting that NF-B inhibitors might

be useful to treat the disease.

Human T cell epitopes of

Mycobacterium tuberculosis areevolutionarily hyperconserved.

Comas, I. et al. Nat. Genet.published online,

doi:10.1038/ng.590 (23 May).

The bits of the M. tuberculosis

bacterium recognized by the human

immune system are highly conserved

across strains. The findings suggest that

the microbe might co-opt the immune

response for its own ends and have

implications for vaccine design.

Bcl-2 and accelerated DNA repair

mediates resistance of hair follicle

bulge stem cells to DNA damage

induced cell death.

Sotiropoulou, P. A. et al. Nat. Cell Biol.published online, doi:10.1038/ncb2059

(16 May).

Stem cells in the skin are resistant to

death in response to DNA damage,

and they repair DNA relatively quickly.

This speed is due to high activity of

nonhomologous end joining, a repair

mechanism that is prone to errors. It

seems that these stem cells are primed

to survive despite damage and tend to

accumulate mutationsa finding with

implications for tumorigenesis and aging.

Chemical genetics strategy identifies

an HCV NS5A inhibitor with a potent

clinical effect.

Gao, M. et al.Nature 465, 96100.

In phase 1 clinical trials, a new drug

substantially reduced the viral load of

chronically infected subjects.

Written by Eva Chmielnicki, Elie Dolgin,

Katherine Gora, Anna Kushnir, Carolina Pola and

Charlotte Schubert

Plaques in

the double

knockout mice.

NLRP3 inflammasomes are required

for atherogenesis and activated by

cholesterol crystals.

Duewell, P. et al.Nature464, 13571361.

The findings provide insight into the long-

standing question of whether cholesterol

is an early trigger of atherosclerosis

or a consequence of the condition.

Cholesterol crystals can activate a protein

complex dubbed the inflammasome,

resulting in inflammation that promotes

atherosclerosis.

CellPress

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