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Let silenced genes speak and cure!
Stem cell researchers at the University of Connecticut (UConn) Health have reversed Prader-Willi syndrome in brain cells growing in the lab! These findings recently published in the journal Human Molecular Genetics. The discovery provides clues that could lead to a treatment for Prader-Willi, a genetic disorder occurring in about one of every 15,000 births. It is the most common genetic cause of life-threatening childhood obesity.
Unlike many genetic syndromes caused by gene mutation, people with Prader Willi often have the right gene available - it is simply silenced.
The gene is silenced because it is on that part of their chromosome inherited from their mother, and for mysterious and unknown reasons our cells use only the father's copy of this particular gene. However, if the father's copy is also missing, the cells can't express the gene at all.
Maeva Langouet, a post-doctoral fellow at UConn Health in the laboratory of Marc Lalande, professor of Genetics and Genome Sciences, wondered along with her colleagues if it was possible to reverse the silenced mother's gene. They noticed that a certain protein, ZNF274, was also involved. ZNF274 silences many genes, but in those cases it usually acts in conjunction with another protein. When observed on the Prader-Willi region of our DNA, ZNF274 seems to act alone.
So Langouet and Lalande took stem cells donated by Prader-Willi patients, and carefully deleted ZNF274. They then encouraged the stem cells to grow into neurons, the long and sinous brain cells. These newly grown cells seemed normal as they grew and developed. Critically, the new cells also expressed the maternal copy of the Prader-Willi region. "We still need to figure out if knocking out ZNF274 is doing anything that might be undesirable", explains Langouet.
Many questions are still unanswered:
Currently, there is no cure for Prader-Willi syndrome, most research is targeted towards treating specific symptoms. For many affected, eliminating some of the most difficult aspects of the syndrome, such as the insatiable appetite, would represent a significant improvement in quality of life and ability to live independently. But, Langouet hopes her research will offer a new approach as well.
Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that is comprised of the zinc-finger protein ZNF274 and the SET domain bifurcated 1 (SETDB1) histone H3 lysine 9 (H3K9) methyltransferase and that silences the maternal alleles at the PWS locus. Here, we have knocked out ZNF274 and rescued the expression of silent maternal alleles in neurons derived from PWS iPSC lines, without affecting DNA methylation at the PWS-Imprinting Center (PWS-IC). This suggests that the ZNF274 complex is a separate imprinting mark that represses maternal PWS gene expression in neurons and is a potential target for future therapeutic applications to rescue the PWS phenotype.
All authors: Maéva Langouët, Heather R Glatt-Deeley, Michael S Chung, Clémence M Dupont-Thibert, Elodie Mathieux, Erin C Banda, Christopher E Stoddard, Leann Crandall, Marc Lalande.
Search terms: alleles, obesity, gene expression, hyperphagia chromosomes, dna methylation, histones, imprinting (psychology), methyltransferase, mothers neurons, prader-willi syndrome, zinc fingers hypotonia, neonatal epigenetics, setdb1 gene The authors have no conflicts of interest or financial disclosures relevant to this manuscript.
The research was funded by the Foundation for Prader-Willi Research, the Cascade Fellowship and the CT Regenerative Medicine Fund.
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Obesity plagues Prader-Willi patients from birth. Foundation for Prader-Willi Research
Image credit: Public domain