Navigation Links
Forcing chromosomes into loops may switch off sickle cell disease
Date:8/14/2014

Scientists have altered key biological events in red blood cells, causing the cells to produce a form of hemoglobin normally absent after the newborn period. Because this hemoglobin is not affected by the inherited gene mutation that causes sickle cell disease, the cell culture findings may give rise to a new therapy for the debilitating blood disorder.

The novel approach uses protein-engineering techniques to force chromatin fiber, the substance of chromosomes, into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin. "We have demonstrated a novel way to reprogram gene expression in blood-forming cells," said study leader Gerd A. Blobel, M.D., Ph.D., who holds the Frank E. Weise III Endowed Chair in Pediatric Hematology at The Children's Hospital of Philadelphia. "If we can translate this approach into the clinic, this may become a new treatment for patients with sickle-cell disease."

Blobel and colleagues, including Wulan Deng, Ph.D., formerly a member of the Blobel laboratory, and current lab member Jeremy W. Rupon, M.D., Ph.D., published their findings online today in Cell.

Key to the researcher's strategy is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin. This has major consequences for patients with the mutation that causes sickle cell disease (SCD).

Fetal hemoglobin is not affected by this mutation. But as adult hemoglobin starts to predominate, patients with the SCD mutation begin to experience painful, sometimes life-threatening disease symptoms as misshapen red blood cells disrupt normal circulation, clog blood vessels and damage organs.

Hematologists have long known that sickle cell patients with elevated levels of fetal hemoglobin compared to adult hemoglobin have a milder form of the disease. "This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it," said Blobel.

In previous research, Blobel's team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the scientists custom-designed zinc fingers to flip the biological switch in blood-forming cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin. The researchers achieved these results in cultured blood cells from adult mice and adult humans.

The next step, said Blobel, is to apply this proof-of-concept technique to preclinical models, by testing the approach in animals genetically engineered to have manifestations of SCD similar to that found in human patients. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

In principle, added Blobel, the forced chromatin looping approach could also be applied to other hemoglobin-related disorders, such as certain forms of thalassemia in which elevated fetal hemoglobin levels might be beneficial.


'/>"/>

Contact: Rachel Salis-Silverman
salis@email.chop.edu
267-426-6063
Children's Hospital of Philadelphia
Source:Eurekalert

Related biology news :

1. Rewriting the history of volcanic forcing during the past 2,000 years
2. Drought, river fragmentation forcing endangered fish out of water, biologist finds
3. Unique chromosomes preserved in Swedish fossil
4. Epigenetic regulation required to ensure correct number of chromosomes
5. Chromosomes show off their shapes
6. UMMS researchers answer century old question about 3D structure of mitotic chromosomes
7. X chromosomes: Undoing a hairpin doubles gene activity
8. A closer look at chromosomes
9. Western aspen trees commonly carry extra set of chromosomes
10. Study of fruit fly chromosomes improves understanding of evolution and fertility
11. Men can rest easy - sex chromosomes are here to stay
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/27/2017)... N.Y. , March 27, 2017  Catholic ... Information and Management Systems Society (HIMSS) Analytics for ... EMR Adoption Model sm . In addition, CHS ... of U.S. hospitals using an electronic medical record ... for its high level of EMR usage in ...
(Date:3/23/2017)... Mar. 23, 2017 Research and Markets has ... Analysis & Trends - Industry Forecast to 2025" report to ... ... a CAGR of around 8.8% over the next decade to reach ... analyzes the market estimates and forecasts for all the given segments ...
(Date:3/20/2017)... March 20, 2017 At this year,s CeBIT Chancellor ... biometrics manufacturer DERMALOG. The Chancellor came to the DERMALOG stand together with ... this year,s CeBIT partner country. At the largest German biometrics company the ... fingerprint, face and iris recognition as well as DERMALOG´s multi-biometrics system.   ... ...
Breaking Biology News(10 mins):
(Date:5/19/2017)... , ... May 19, 2017 , ... ... Proof-of-Concept Program. Academic researchers with technologies ripe for commercialization, and who are ... and Delaware, are encouraged to submit proposals. QED, now in its tenth round, ...
(Date:5/18/2017)... ... May 18, 2017 , ... Lajollacooks4u ... Cooking Challenge is a two-hour team-building package designed for groups of 10-30 people. ... Jodi Abel, which include items, such as Blackened Shrimp with Edamame Salad, Pizza ...
(Date:5/18/2017)... ... May 17, 2017 , ... NDA Partners Chairman Carl ... CEO of Eurofins Advantar Laboratories and President of Pharmaceutical Development Business Unit of Cardinal ... at Eurofins and Cardinal Health, he was former Chief Operating Officer at Anaborex, Senior ...
(Date:5/18/2017)... ... May 17, 2017 , ... Cognition ... and commercialization, has just released version 9.0 of the Cognition Cockpit platform. , ... of Cockpit,” says David Cronin, CEO of Cognition. “We’re thrilled to finally be ...
Breaking Biology Technology: