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:5/20/2016)... 2016  VoiceIt is excited to announce its ... By working together, VoiceIt and VoicePass will ... VoicePass take slightly different approaches to voice biometrics, ... and usability. ... partnership. "This marketing and technology partnership ...
(Date:5/3/2016)...  Neurotechnology, a provider of high-precision biometric identification ... Identification System (ABIS) , a complete system for ... can process multiple complex biometric transactions with high ... face or iris biometrics. It leverages the core ... MegaMatcher Accelerator , which have been used in ...
(Date:4/26/2016)... Research and Markets has announced ... 2016-2020"  report to their offering.  , ,     (Logo: ... analysts forecast the global multimodal biometrics market to ... period 2016-2020.  Multimodal biometrics is being ... the healthcare, BFSI, transportation, automotive, and government for ...
Breaking Biology News(10 mins):
(Date:5/25/2016)... ... May 25, 2016 , ... Founder ... double board-certified in surgery and surgery of the hand by the National Board ... stranger to going above and beyond in his pursuit of providing the most ...
(Date:5/25/2016)... LAKE CITY, UTAH. (PRWEB) , ... May 25, 2016 , ... ... efficiencies in healthcare information exchange, today announced that Charles W. Stellar has been named ... as WEDI’s interim CEO since January 2016. As an executive leader with more than ...
(Date:5/24/2016)... ... 24, 2016 , ... Cell therapies for a range of ... research at Worcester Polytechnic Institute (WPI) that yielded a newly patented method of ... The novel method, developed by WPI faculty members Raymond Page, PhD, professor of ...
(Date:5/24/2016)... ... May 24, 2016 , ... Media Cybernetics, ... new Media Cybernetics corporate branding reflects a results-driven revitalization for a company with ... The re-branding components include a crisp, refreshed logo and a new web presence. ...
Breaking Biology Technology: