PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Gene-silencing strategy opens new path to understanding Down Syndrome

Genome-wide changes result from silencing extra chromosome, scientists report at ASHG 2013

2013-10-23
(Press-News.org) Contact information: Cathy Yarbrough
press@ashg.org
858-243-1814
American Society of Human Genetics
Gene-silencing strategy opens new path to understanding Down Syndrome Genome-wide changes result from silencing extra chromosome, scientists report at ASHG 2013 The first evidence that the underlying genetic defect responsible for trisomy 21, also known as Down syndrome, can be suppressed in laboratory cultures of patient-derived stem cells was presented today (Oct. 22) at the American Society of Human Genetics 2013 annual meeting in Boston.

People with Down syndrome are born with an extra chromosome 21, which results in a variety of physical and cognitive ill effects. In laboratory cultures of cells from patients with Down syndrome, an advanced genome editing tool was successfully used to silence the genes on the extra chromosome, thereby neutralizing it, said Jeanne Lawrence, Ph.D., Professor of Cell & Developmental Biology at the University Massachusetts Medical School, Worcester, MA.

Dr. Lawrence and her team compared trisomic stem cells derived from patients with Down syndrome in which the extra chromosome 21 was silenced to identical cells from patients that were untreated. The researchers identified defects in the proliferation, or rapid growth, of the untreated cells and the differentiation, or specialization, of untreated nervous system cells. These defects were reversed in trisomic stem cells in which the extra chromosome 21 was muted.

"Silencing of trisomy 21 by manipulation of a single gene in living cells in laboratory cells surmounts the first major obstacle to development of potential 'chromosome therapy,'" said Dr. Lawrence, whose presentation today provided an update to the results that she and her colleagues reported earlier this year in the journal Nature (Jiang et al. 2013)

In her ASHG presentation, Dr. Lawrence described the use of the novel editing tool to examine changes in gene expression that result from the silencing of the extra chromosome. The changes in gene expression were not limited to chromosome 21 but were genome-wide.

"In fact, the results indicate that the most prominent changes are in genes not encoded on chromosome 21," said Dr. Lawrence, who also provided more perspective about the various avenues of research that the results have created and that are now being and will be pursued in her lab.

The approach used by Dr. Lawrence and her team was inspired by the natural process that silences one copy of the female mammals' two sex-determining X chromosomes during embryonic development. In males, the sex-determining chromosomes are X and Y, and gene silencing helps maintain similar expression patterns of X chromosome genes in females and males.

To understand this biological process, Dr. Lawrence and her collaborators several years ago began studying the X-inactivation gene (XIST), which encodes a large non-coding RNA molecule. In laboratory cultures of cells, this molecule was shown to cover the surface of one of the X chromosomes of female mammals. XIST's actions permanently blocked the expression, or activity level, of the genes on the affected X chromosome.

Dr. Lawrence and her team mimicked this natural process by inserting the XIST gene into the gene-rich core of the extra chromosome 21 in lab cultures of pluripotent stem cells from patients with Down syndrome. Before taking this step, they first demonstrated that a large transgene could be successfully inserted at a specific site by using zinc-finger nuclease technology.

In the laboratory cells, they found that the RNA from the inserted XIST gene induced a host of epigenetic modifications that transcriptionally silenced the genes of the extra chromosome 21.

"Remarkably, the RNA localized across and comprehensively silenced one of the three chromosome 21s, as shown by eight different methods, including molecular, cytological and genomic," said Dr. Lawrence.

The researchers found that APP, which encodes beta-amyloid precursor protein, was among the silenced genes on the XIST-coated chromosome 21. Mutations in APP cause the accumulation of beta-amyloid that leads to early-onset familial Alzheimer's disease, Dr. Lawrence said. APP over-expression is linked to the Alzheimer's disease that occurs in many patients with Down syndrome.

"The results show the clear promise of this new strategy as a novel approach to identify the poorly understood cellular pathways deregulated in Down syndrome and creates the opportunity to derive and study various patient-compatible cell types potentially relevant to Down syndrome therapeutics," she noted.

"This general strategy could be extended to study other chromosomal disorders such as trisomy 13 and 18, which are usually fatal in the first one to two years of life," Dr. Lawrence added.

### Title of the abstract: "Translating dosage compensation to Trisomy 21: a novel approach to Down syndrome."

ABOUT ASHG:

The American Society of Human Genetics is the primary professional membership organization for nearly 8,000 human genetics specialists worldwide. The ASHG Annual Meeting is the world's largest gathering of human genetics professionals and a forum for renowned experts in the field. For more information about ASHG, visit: http://www.ashg.org.


ELSE PRESS RELEASES FROM THIS DATE:

HIV elimination in South Africa could be achieved by current treatment policy

2013-10-23
HIV elimination in South Africa could be achieved by current treatment policy The current antiretroviral treatment policy in South Africa could lead to elimination of HIV within the country over the next 24 to 34 years, but a universal test and treat (UTT) ...

RNA signatures from suspected TB patients could form the basis of a diagnostic test

2013-10-23
RNA signatures from suspected TB patients could form the basis of a diagnostic test A set of RNA transcriptional signatures expressed in the blood of patients might provide the basis of a diagnostic test that can distinguish active tuberculosis (TB) from ...

Xpert MTB/RIF test may improve diagnosis of tuberculous meningitis in HIV-infected individuals

2013-10-23
Xpert MTB/RIF test may improve diagnosis of tuberculous meningitis in HIV-infected individuals Tuberculous meningitis (TBM) is a serious and often fatal illness that is difficult to diagnose particularly in resource-poor areas and is especially common ...

Delaying gratification, when the reward is under our noses

2013-10-23
Delaying gratification, when the reward is under our noses How can some people resist the attraction of immediate pleasures and pursue long-term goals, while others easily succumb and compromise their ultimate expectations? A recent study led by researchers at the Brain ...

Internet users more likely to engage in cancer-preventive behaviors

2013-10-23
Internet users more likely to engage in cancer-preventive behaviors PHILADELPHIA — Older men and women who used the internet were more likely to participate in screening for colorectal cancer, participate in physical activities, eat healthily, ...

Flu vaccine associated with lower risk of cardiovascular events

2013-10-23
Flu vaccine associated with lower risk of cardiovascular events Receiving an influenza vaccination was associated with a lower risk of major adverse cardiovascular events such as heart failure or hospitalization for heart attack, with the greatest treatment ...

Brief risk-reduction counseling at time of HIV testing does not result in reduction in rate of STIs

2013-10-23
Brief risk-reduction counseling at time of HIV testing does not result in reduction in rate of STIs Brief risk-reduction counseling at the time of a rapid human immunodeficiency virus (HIV) test was not effective for reducing new sexually transmitted infections ...

Intranasal application of hormone appears to enhance placebo response

2013-10-23
Intranasal application of hormone appears to enhance placebo response The hormone oxytocin may mediate processes such as empathy, trust, and social learning. These are key elements of the patient-physician relationship, which is an important mediator of ...

WSU researchers link DDT and obesity

2013-10-23
WSU researchers link DDT and obesity Effects seen across generations PULLMAN, Wash.—Washington State University researchers say ancestral exposures to environmental compounds like the insecticide DDT may be a factor in high rates of obesity. The finding comes ...

Internet therapy may help postnatal depression

2013-10-23
Internet therapy may help postnatal depression Researchers at the University of Exeter have teamed up with online forum Netmums in a pilot study which has shown that postnatal depression can be treated effectively using online therapy. Rates of postnatal depression ...

LAST 30 PRESS RELEASES:

Attitudes, not income, drive energy savings at home

The playbook for perfect polaritons

‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell

Solar-powered method lights the way to a ‘de-fossilized’ chemical industry

Screen time linked to lower academic achievement among Ontario elementary students

One-year outcomes after traumatic brain injury and early extracranial surgery in the TRACK-TBI Study

Enduring outcomes of COVID-19 work absences on the US labor market

Affirmative action repeal and racial and ethnic diversity in us medical school admissions

Cancer progression illuminated by new multi-omics tool

Screen time and standardized academic achievement tests in elementary school

GLP-1RA order fills and out-of-pocket costs by race, ethnicity, and indication

Study finds HEPA purifiers alone may not be enough to reduce viral exposure in schools

UVA Health developing way to ID people at risk of dangerous lung scarring even before symptoms appear

How can we know when curing cancer causes myocarditis?

Male infertility in Indian men linked to lifestyle choices and hormonal imbalances

An acoustofluidic device for sample preparation and detection of small extracellular vesicles

The advent of nanotechnology has ushered in a transformative era for oncology, offering unprecedented capabilities for targeted drug delivery and controlled release. This paradigm shift enhances thera

A prototype LED as thin as wallpaper — that glows like the sun

Transnational electoral participation of undocumented Mexican immigrants in the US

A new method to build more energy-efficient memory devices for a sustainable data future

Freely levitating rotor spins out ultraprecise sensors for classical and quantum physics

‘Chinese lantern’ structure shifts into more than a dozen shapes for various applications

Towards light-controlled electronic components

Tiny architects, titanic climate impact: scientists call for October 10 to become International Coccolithophore Day

Stress sensitivity makes suicidal thoughts more extreme and persistent among the university population

Lessons from Ascension’s shark troubles could help boost conservation

Fire provides long-lasting benefits to bird populations in Sierra Nevada National Parks

Menstrual cycle affects women’s reaction time but not as much as being active

Housing associations more effective than government in supporting unemployed in deprived areas

Biochar helps composting go greener by cutting greenhouse gas emissions

[Press-News.org] Gene-silencing strategy opens new path to understanding Down Syndrome
Genome-wide changes result from silencing extra chromosome, scientists report at ASHG 2013