Navigation Links
Forcing chromosomes into loops may switch off sickle cell disease

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
Children's Hospital of Philadelphia

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:
(Date:11/19/2015)... MOUNTAIN VIEW, Calif. , Nov. 19, 2015 /PRNewswire/ ... authentication market, Frost & Sullivan recognizes BIO-key with the ... Strategy Leadership. Each year, Frost & Sullivan presents this ... comprehensive product line catering to the needs of the ... which the product line meets and expands on customer ...
(Date:11/18/2015)... 2015 --> ... market report titled  Gesture Recognition Market - Global Industry ... 2021. According to the report, the global gesture recognition market was valued ... reach US$29.1 bn by 2021, at a CAGR of ... America dominated the global gesture recognition market ...
(Date:11/17/2015)... Nov. 17, 2015  Vigilant Solutions announces today that ... Board of Directors. --> ... retiring from the partnership at TPG Capital, one of ... over $140 Billion in revenue.  He founded and led ... the TPG companies, from 1997 to 2013.  In his ...
Breaking Biology News(10 mins):
(Date:11/30/2015)... Germany , November 30, 2015 ... Vienna, Austria to be held December ... (ECNR) in Vienna, Austria to ... wholly owned subsidiary of Vycor Medical, Inc. ("Vycor") (OTCQB: VYCO), ... NovaVision Therapy Suite at the 3rd European Congress of ...
(Date:11/27/2015)... , Nov. 27, 2015 /PRNewswire/--  Mallinckrodt plc (NYSE: ... today that it has closed the sale of its ... Guerbet (GBT- NYSE Euronext) in a transaction valued at ... manufacturing facilities and a total of approximately 1,000 employees ... St. Louis area. This entire ...
(Date:11/25/2015)... , November 26, 2015 ... Biobanking Market 2016 - 2020 report analyzes that ... integrity and quality in long-term samples, minimizing manual ... cost-effectiveness. Automation minimizes manual errors such as mislabeling ... efficiency. Further, it plays a vital role in ...
(Date:11/25/2015)... 25, 2015  Neurocrine Biosciences, Inc. (Nasdaq: NBIX ... and CEO of Neurocrine Biosciences, will be presenting at ... New York . .   ... approximately 5 minutes prior to the presentation to download ... presentation will be available on the website approximately one ...
Breaking Biology Technology: