CIRM-funded team traces molecular basis for differences between human and chimp face

So similar yet so different
Whenever I go to the zoo, I could easily spend my entire visit hanging out with our not-so-distant relatives, the chimpanzees. To say we humans are similar to them is quite an understatement. Sharing 96% of our DNA, chimps are more closely related to us than they are to gorillas. And when you just compare our genes – that is, the segments of DNA that contain instructions for making proteins – we’re even more indistinguishable.

Chimps and Humans: So similar yet so different

Chimps and Humans: So similar yet so different

And yet you wouldn’t mistake a human for a chimp. I mean, I do have hairy arms, but they’re not that hairy. So what accounts for our very different appearance if our genes are so similar?

To seek out answers, a CIRM-funded team at Stanford University used both human and chimp induced pluripotent stem cells (iPSCs) to derive cranial neural crest cells (CNCCs). This cell type plays a key role in shaping the overall structure of the face during the early stages of embryo development. In a report published late last week in Cell, the team found differences, not in the genes themselves, but in gene activity between the human and chimp CNCCs.

Enhancers: Volume controls for your genes
Pinpointing the differences in gene activity relied on a comparative analysis of so-called enhancer regions of human and chimp DNA. Unlike genes, the enhancer regions of DNA do not provide instructions for making proteins. Instead they dictate how much protein to make by acting like volume control knobs for specific genes. A particular volume level, or gene activity, is determined by specific combinations of chemical tags and DNA-binding proteins on an enhancer region of DNA.

Enhancers: DNA segments that act like a volume control know for gene activity (Image source: xxxx)

Enhancers: DNA segments that act like a volume control knobs for gene activity (Image source: FANTOM Project, University of Copenhagen)

The researchers used several sophisticated lab techniques to capture a snapshot of this enhancer tagging and binding in the CNCCSs. They mostly saw similarities between human and chimp enhancers but, as senior author Joanna Wysocka explains in a Stanford University press release, they did uncover some differences:

“In particular, we found about 1,000 enhancer regions that are what we termed species-biased, meaning they are more active in one species or the other. Interestingly, many of the genes with species-biased enhancers and expression have been previously shown to be important in craniofacial development.”

PAX Humana: A genetic basis for our smaller jawline and snout?
For example, their analysis revealed that the genes PAX3 and PAX7 are associated with chimp-biased enhancer regions, and they had higher levels of activity in chimp CNCCs. These results get really intriguing once you learn a bit more about the PAX genes: other studies in mice have shown that mutations interfering with PAX function lead to mice with smaller, lower jawbones and snouts. So the lower level of PAX3/PAX7 gene activity in humans would appear to correlate with our smaller jaws and snout (mouth and nose) compared to chimps. Did that just blow your mind? How about this:

The researchers also found a variation in the enhancer region for the gene BMP4. But in this case, BMP4 was highly related to human-biased enhancer regions and had higher activity in humans compared to chimps. Previous mouse studies have shown that forcing higher levels of BMP4 specifically in CNCCs leads to shorter lower and upper jawbones, rounder skulls, and eyes positioned more to the front of the face. These changes caused by BMP4 sound an awful lot like the differences in human and chimp facial structures. It appears the Stanford group has established a terrific strategy for tracing the genetic basis for differences in humans and chimps.

So what’s next? According to Wysocka, the team is digging deeper into their data:

“We are now following up on some of these more interesting species-biased enhancers to better understand how they impact morphological differences. It’s becoming clear that these cellular pathways can be used in many ways to affect facial shape.”

And in the bigger picture, the researchers also suggest that this “cellular anthropology” approach could also be applied to a human to human search for DNA enhancer regions that play a role in the variation between healthy and disease states.

Scientists Sink their Teeth into Stem Cell Evolution

Sometimes, answers to biology’s most important questions can be found in the most unexpected of places.

As reported in the most recent issue of the journal Cell Reports, researchers at the University of California, San Francisco (UCSF) and the University of Helsinki describe how studying fossilized rodent teeth has helped them inch closer to grasping the origins of a particular type of stem cell.

Rodents' ever-growing teeth hold clues to the evolution of stem cells, according to a new study.

Rodents’ ever-growing teeth hold clues to the evolution of stem cells, according to a new study.

Understanding the microenvironment that surrounds each stem cell, known as a stem cell niche, is key to grasping the key mechanisms that drive stem cell growth. But as UCSF scientist Ophir Klein explained, many aspects remain a mystery.

“Despite significant recent strides in the field of stem cell biology, the evolutionary mechanisms that give rise to novel stem cell niches remain essentially unexplored,” said Klein, who served as the study’s senior author. “In this study, we have addressed this central question in the fields of evolutionary and developmental biology.”

In this study, Klein and his team focused on the teeth of extinct rodent species. Why? Because many species of rodent—both extinct species and those alive today—have what’s called ‘ever-growing teeth.’

Unlike most mammals, including we humans, the teeth of some rodent species continue to grow as adults—with the help of stem cell ‘reservoir’ hidden inside the root.

And by analyzing the fossilized teeth of extinct rodent species, the researchers could gain some initial insight into how these reservoirs—which were essentially a type of stem cell niche—evolved.

Most stem cell niche studies take cell samples from hair, blood or other live tissue. Teeth, as it turns out, are the only stem cell niches that can be found in fossil form.

In fact, teeth are “the only proxy…for stem cell behavior in the fossil record,” says Klein.

After analyzing more than 3,000 North American rodent fossils that varied in age between 2 and 50 million years ago, the researchers began to notice a trend. The earlier fossils showed short molar teeth. But over the next few million years, the molars began to increase in length. Interestingly, this coincided with the cooling of the climate during the Cenozoic Period. The types of food available in this cooler, drier climate likely became tougher and more abrasive—leading to evolutionary pressures that selected for longer teeth. By 5 million years ago, three-quarters of all species studied had developed the capability for ever-growing teeth.

The team’s models suggest that this trend has little chance of slowing down, and predicts that more than 80% of rodents will adopt the trait of ever-growing teeth.

The next step, says Klein, is to understand the genetic mechanism that is behind the evolutionary change. He and his team, including the study’s first author Vagan Tapaltsyan, will study mice to test the link between the genetics of tooth height and the appearance of stem cell reservoirs.

Stem cell stories that caught our eye: gene editing tools, lung repair in COPD and big brains

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Correcting the genetic error in sickle-cell disease might be as simple as editing the text.

Correcting the genetic error in sickle-cell disease might be as simple as editing the text [Credit: Nature News].

Review of the many ways to edit defective genes. Nature’s news section did a nice review of the many ways blood-forming stem cells can be genetically altered to correct diseases caused by a single mutation. If you have been following the recently booming field of gene therapy, you may have a hard time keeping all the items in the gene editing toolbox straight. The Nature author provides a rundown on the leading contenders—viral vectors, zinc fingers, TALENs and CRISPRs. Early in the piece she describes why researchers are so excited by the field.

“Although most existing treatments for genetic diseases typically only target symptoms, genetic manipulation or ‘gene therapy’ goes after the cause itself.”

Much of the article talks about work by CIRM grantees. It describes work by Don Kohn at the University of California, Los Angeles, on vectors and zinc fingers, as well as work by Juan Carlos Izpisua Belmonte at the Salk Institute using TALENS and CRISPRs. We explain Kohn’s work treating sickle cell disease in our Fact Sheet.

Getting lungs to repair themselves. A research team at Jackson Labs in Maine has isolated a stem cell in lungs that appears to be able to repair damage left behind by severe infections. They hope to learn enough about how those stem cells work to enlist them to repair damage in diseases like Chronic Obstructive Pulmonary Disease (COPD).

They published the work in Nature and ScienceDaily picked up the lab’s press release. It quotes the lead researcher, Wa Xian on the hope they see down the road for the 12 million people in the U.S. with COPD:

“These patients have few therapeutic options today. We hope that our research could lead to new ways to help them.”

Making middle-man cells more valuable. The University of Wisconsin lab of Jamie Thomson, where human embryonic stem cells (ESCs) were first isolated, has found a way to make some of the offspring of those stem cells more valuable.

We have often written that for therapy, the desired cell to start with is not an ESC or even the end desired adult tissue, but rather a middleman cell called a progenitor. But those cells often don’t renew, or replicate themselves, very well in the lab. Ideally researchers would like to have a steady supply of progenitor cells that could be pushed to mature further only when needed. The Thomson lab found that by manipulating a few genes they could arrest the development of progenitors so they constantly renew themselves. ScienceNewsline picked up the press release from the University’s Morgridge Institute that houses the Thomson lab.

Link found to human’s big brains. A CIRM-funded team at the University of California, San Francisco, isolated a protein that seems to be responsible for fostering the large brain size in humans compared with other animals. Human brain stem cells need the protein, dubbed PDGFD, to reproduce.

The team found that the protein acts on parts of the brain that have changed during mammalian evolution. It is not active at all in mice brains, for example. So, if someone accuses you of being a smart aleck just tell them you can’t help it, it’s your PDGFD. HealthCanal ran the university’s press release, which provides a lot more detail of how the protein actually helps give us big heads.

Don Gibbons