Epigenetic therapies — targeting enzymes that alter what genes are turned on or off in a cell — are of growing interest in oncology as a way to make cancers less aggressive or less malignant. But now, at least one epigenetic therapy that had looked promising for lung cancer appears to boost the cancer stem cells that are believed to drive tumors. A study published today in Nature Communications also identifies a strategy that reduces these stem cells, curbing lung cancer in mice. …
A biological process known as genomic imprinting helps control early mammalian development by turning genes on and off as the embryo and placenta grow. Errors in genomic imprinting can cause severe disorders and profound developmental defects that lead to lifelong health problems, yet the mechanisms behind these critical gene-regulating processes — and the glitches that cause them to go awry — have not been well understood.
Now, scientists at Harvard Medical School (HMS) and Boston Children’s Hospital have identified a mechanism that regulates the imprinting of multiple genes, including some of those critical to placental growth during early embryonic development in mice. The results were reported yesterday in Nature.
“A gene that is turned off by epigenetic modifications can be turned on much more easily than a gene that is mutated or missing can be fixed,” said Yi Zhang, PhD, a senior investigator in the Boston Children’s Program in Molecular and Cellular Medicine, a professor of pediatrics at HMS and a Howard Hughes Medical Institute investigator. “Our discovery sheds new light on a fundamental biological mechanism and can lay the groundwork for therapeutic advances.” …
Why do some people seem to be prone to weight gain? Obesity has been linked to a variety of genetic changes, yet these differences don’t fully explain the variation in people’s body mass index (BMI). “Even though we’ve genetically sequenced more and more people at greater and greater breadth and depth, we haven’t completely explained who develops obesity and why,” says Michael Mendelson, MD, ScM, a pediatric cardiologist with Boston Children’s Hospital’s Preventive Cardiology Program.
Nor do prior studies explain why some overweight people develop health complications from obesity, like cholesterol problems, diabetes, hypertension and heart disease, while others don’t. Now comes strong evidence that an important factor is DNA methylation — a so-called epigenetic modification that influences whether genes are turned on or off. …
Growing up in the San Francisco area, Cigall Kadoch, PhD, had a passion for puzzles. The daughter of a Moroccan-born, Israeli-raised father and a mother from Michigan who together developed an interior design business, Kadoch excelled in school and pretty much everything else. Above all, she loved to solve brain-teasers.
For Kadoch, the Rubik’s cube represents a love of puzzles, as well as the structure of the protein complexes she studies in her research at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber Chief of Staff Stephen Sallan, MD, describes her as “addicted to discovery.”
In high school, however, Kadoch came up against a problem that defied solution. Breast cancer took the life of a beloved family caretaker who had nurtured her interests in science and nature. She knew little about cancer except that it took lives far too early.
“I was deeply saddened and very frustrated at my lack of understanding of what had happened,” recalls Kadoch. “I thought to myself, cancer is a puzzle that isn’t solved, let alone even well-defined, and I want to try. As naïve a statement as that was, it was a defining moment—one which I never could have predicted would actually shape my life’s efforts.” …
“Genome” has been the biggest word in cancer research in the last decade. Thanks largely to the high throughput and relatively low cost of “next generation” DNA-sequencing technologies, researchers have screened thousands of tumors for gene mutations that could explain their malignant properties and reveal possible treatment targets.
Sequencing of adult tumors has revealed a broad spectrum of cancer-causing gene mutations. Childhood tumors, by contrast, have turned out to be relatively simple from a genomic point of view. By and large, they harbor few mutations in genes that code for relatively “druggable” targets with discrete effects, like kinases.
“Pediatric tumors are very ‘pure,’ with very low mutation rates,” says Carlos Rodriguez-Galindo, MD, director of the Solid Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “To really understand the nature of pediatric cancer, we need to turn to epigenetics and gene regulation.”
Rodriguez-Galindo is not alone in this view. There is a trend afoot in pediatric cancer research: the study of gene regulation and epigenetics is beginning to overshadow classic tumor genetics and genomics. …
For decades, the central paradigm behind the treatment of most tumors has been “get it out”—or, if you can’t, kill it. But note that I said most tumors. For some, the best course isn’t necessarily one that focuses on killing the tumor, but one that also makes it grow up.
The cells of tumors like neuroblastoma or some kinds of acute leukemia aren’t necessarily wildly growing invaders full of murderous mutations. Rather, they’re immature. Instead of following the normal developmental path from stem cell to mature nerve (in the case of neuroblastoma) or white blood cell (in leukemia), something prevents the cells from maturing fully.
Mature or not, the cells can still grow without pause, quickly forming tumors or crowding healthy cells out.
The techniques for making cancer cells mature—or differentiate—differ greatly from those for making cancer cells die. But they hold promise for better, less toxic cures, especially for children with neuroblastoma, which next to brain tumors is the most common solid tumor of children. …
There are several ways to reprogram skin cells into induced pluripotent stem (iPS) cells – cells that behave like embryonic stem cells, and which could help better understand the genetic basis of and develop new treatments for different diseases.
The major methods scientists use now include using viruses to deliver reprogramming genes or using RNAs to produce the necessary proteins without the genes. Different methods have different advantages and disadvantages, and some are more efficient than others.
What’s common across all of the methods is that they rely on four proteins to turn back the cellular clock – c-Myc, Klf4, Oct4, and Sox2. Less understood is whether enzymes that modify chromatin (the DNA-plus-protein package that constitutes our genome) play any role in the reprogramming process. These enzymes manage and control the cell’s epigenetic code – the layer of control that helps cells fine-tune gene expression by adding and removing small chemical tags to genes and proteins.
“During iPS reprogramming, a cell’s epigenetic code gets completely rewritten,” says George Q. Daley, director of the Stem Cell Transplantation Program at Children’s Hospital Boston. “But how the cell’s epigenetic enzymes influence the reprogramming process has been a mystery.” …
In the 40 years of the war on cancer, there is probably no greater success story than that of childhood leukemias. Once nearly uniformly fatal, some forms of acute lymphoblastic (ALL) and acute myeloid (AML) leukemias can now be cured in 80 or even 90 percent of cases.
The prognosis for the remaining 10 to 20 percent is not as good, especially if the cancer involves a reshuffling or rearrangement of the mixed lineage leukemia (MLL) gene. “We still only achieve about 50 percent success in treating these MLL-rearranged leukemias,” according to Scott Armstrong, a pediatric oncologist at Children’s and Dana-Farber Cancer Institute. “We need to find better ways of caring for these patients.”
While the genome’s As, Ts, Cs, and Gs hold the instructions for making proteins, how does a cell know when to read a gene? And could it relate to developmental disorders?
These gene-reading instructions are encoded in our epigenome, a set of factors that give our cells exquisite control over when and where to turn individual genes on and off. This control involves a delicate and complex dance between DNA and proteins called histones – DNA wraps itself around histones to create a complex called chromatin – as well as the many different types of epigenetic tags.
Yang Shi, of the Division of Newborn Medicine at Children’s Hospital Boston, wants to understand what happens when the genome doesn’t read the epigenome’s instructions correctly, which in the developing brain can cause intellectual disabilities. …
Adenine and thymine, cytosine and guanine. We all learned the names of the four DNA bases in high school biology class. But, just like the list of planets, the list of bases may not be set in stone.
Over the years, epigenetics researchers have identified two alternate forms of cytosine whose biology differs enough from that of their parent base that may count as fifth and sixth DNA bases. These additional cytosines, called 5-methylcytosine (5mc) and 5-hydroxymethylcytosine (5hmc), each have a group of atoms called a methyl group added onto their central ring, a feature normal cytosine lacks.
Apart from making biology textbook editors very unhappy, these two bases may play unique roles in biology. Adding methyl groups (or methylation “marks”) to cytosines and other components of the genome is a well-known epigenetic mechanism that gives the cell exquisite control of gene activity, which in turn greatly influences how the cell will behave. For instance, patterns of methylation marks on the genes of embryonic stem (ES) cells are linked the cells’ ability to develop into more mature cells. And the genomes of cancer cells often have methylation marks in the wrong places. …