5 Amazing Feats Performed by “Meta-Genes”

[Image via the NIH Image Gallery. Photo by Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths. Full video, complete with narration here.] 

Under the Radar: A series of listicles about biology concepts you definitely won’t find in newspaper headlines.

#1: Be a Navigation App for Immune Cells

Natural killer cells, or “NK cells” are the human body’s best defense against cancer.  While other types of immune cells often ignore tumor cells, natural killer cells specialize in finding and destroying human cells that look either infected or like cancer mutants. In leukemia patients,  a higher number of active natural killer cells ups the patient’s chances for survival, so much so that  researchers are experimenting with transfusing NK cells into patients.

Just one problem there: Active natural killer cells die without a strong support network.

Dormant NK cells can survive in the bloodstream for a long time, but once activated, natural killers have to make a b-line for cells carrying a marker called IL-15 or die,  but until a study in Monday’s edtion of PNAS , no one knew how natural killers knew to look for IL-15. The study, led by Vanderbilt immunologist Eric Sebzda and grad student Whitney Rabacal, traced NK cells’ IL-15 homing ability back to a biochemical with the horrendous name “Kruppel-like Factor 2” (KLF2).

KLF2, oddly enough, also exerts a strong navigational influence on the immune system’s T-cells and B-cells.  Even though all three types of cells fall under the “white blood cell” umbrella, the notion that one protein could control navigation in all three is pretty weird.  Crawling and navigating are complex tasks, requiring coordination between dozens of genes. “[NK cell migration] is totally different from how t-cells and b-cells circulate,” Sebzda said.

Additionally, taking away KLF2 has distinctive effects on each type of cell: KLF2-less t-cells vacate the central body and crawl out to lab mice’s fingers and toes, KLF2-less b-cells all congregate at the spleen (which creates some serious problems for those lab mice), and KLF2-less natural killers end up dying alone.

So KLF2 could be super-useful for improving cancer immunotherapy. But why is KLF2 so versatile in the first place?

The answer lies in KLF2’s ability to bind to a certain recurring DNA base pair sequence, one that presumably earmarks the genes needed in each immune system navigation system, and it’s far from the only protein with such abilities…

Meet the Bogeys: Transcription Factors

If a genome is like a text, it’s one that can be read in many different ways.  Every gene serves as a template for a piece of cell machinery, but thousands of biochemicals that play a role in telling the cell which gene template to use when and how many copies to make.

Some of those gene-controlling molecules are based on gene templates themselves. First and foremost among the “meta-genes” are the transcription factors,  like KLF2, each of which can land on  its own DNA pattern.

The sequences each transcription factor can land on are pretty short.  A 9-base-pair sequence like”CATGATTAT” would recur many, many times within a 3-billion-base-pair-containing human genome, so a “CATGATTAT-seeking transcription factor would be able to land on any exposed “CATGATTAT” and influence the expression of nearby genes. (Some TFs boost gene expression; others block it.)

Transcription factors, like alternative splicing, are one of the built-in “hacks” that biology uses to control its traits. (And,as such, are part of a growing field called epigenetics.) Transcription factors (or “TFs“)  are particularly adept at switching several different genes on and off in one fell swoop.

(I always kind of imagine transcription factors as being kind of like the Rings of Power in Lord of the Rings. All genes have some power, but like The One Ring, transcription factors have the power to manipulate the other genes. Also, being a transcription-factor specialist renders most of the TF scientists pretty much invisible in science news media….Key difference: There is no one transcription factor gene “to rule them all”. It’s more like a couple thousand TFs to each rule a whole bunch of genes. Unfortunately, that’s less punchy.)

Here are just a few things transcription factors can do:

 

#2: Tell Neurons Where to Grow

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Have you ever wondered how your body makes sure all of the neurons that control your thumbs, forefingers, and toes are wired up correctly?

Every individual motor neuron follows a unique route from the spinal cord to the muscle fiber it controls. (For the neurons in your feet, that means threading a four-and-a-half-foot-long nerve fiber from the base of your spinal cord to the soles of your feet.)  Neuroscientists have long been puzzled about how genetically identical proto-motor-neurons manage to navigate budding embryonic limbs.

Last May, a team led by Jonathan Enriquez, a postdoc in Richard S. Mann’s lab at Columbia- captured full-length images of the 7 motor neurons that control the legs in fruitflies, and found that each of the 7 neurons exhibited a unique combination of transcription factors

When they altered the transcription factor codes in mutant fly embryos, the neurons connected to different muscle fibers in the legs. (Flies with the mis-connected neuron weave from side-to-side when they run.  The mutant flies, which were otherwise healthy, could walk in straight lines; they just couldn’t run without weaving and zig-zagging all over the place.)

Enriquez and posse concluded that the transcription factor codes are kind of like a combination lock; nascent neurons need to receive three or four different transcription factors in a specific order before they know whether they connect to the kneecap or the pinky toe.

#3: Make an Ordinary Bee a Queen

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[“Bee Peeking” photo by Gordon via Creative Commons/Flickr]

Some bees live in colonies with a queen-– a lone female who produces all of the eggs on the colony’s behalf– and hundreds or thousands of worker bee sisters who support her but cannot reproduce. Other bees lead a more typical lifestyle, with no queens and no workers, just bees.

The weird thing is: The Queen Bee System– eusociality in technical parlance– has evolved more than once. It’s a complicated change. Worker bees cannot reproduce (except for rare circumstances where the queen gets killed or dies), so the transition from solitary bee-hood to queenly hivedom would have to happen pretty quickly or else, the bee species would be wiped out.

“There have been a lot of success stories in assessing fitness [of eusocial species] from a behavioral ecology standpoint, and most of them have sort of ‘black-boxed’ the mechanisms,” said biologist/bee specialist Karen Kapheim of Utah State University.

A study by Kapheim and her colleagues revealed that the contents of the “black box” of bee social structure vary widely depending on the bee. Kapheim and her colleagues analyzed genomes from ten bee species and found that each of the eusocial groups used a different set of genes to decide who is queen.

But guess what all of the Queen-making mechanisms have in common….Yup. Transcription factors.

The differences between queen bees and their worker daughters and sisters aren’t in DNA base pairs; they’re in the transcription factors that decide when certain genes get expressed.  For female bees, at least, there truly are a handful of (transcription-factor-coding) genes that rule them all.

 

[Update 5/18/16:  Kapheim sent me an email saying, “I also would de-emphasize the role of different genes/ TFs in “deciding who is queen”, but rather that these seem to be involved in the overall social patterns of the species.”…Which is an excellent point. I plead “hazard of writing listicle headlines.”]

 

#4: Broker peace between self-attacking T-cells and bystander cells

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[Photo via NIAID and Flickr]

Autoimmune diseases suck. They’re subtly-disabling, difficult to diagnose, and even harder to treat. (Plus, they’re on the rise.)

Fortunately,  our immune systems have tiny voices of reason called regulatory T-cells or “T-regs”.  They patrol our bloodstreams, doing their best to make sure that other immune cells aren’t attacking undeserving human cells. When autoimmune diseases like asthma, allergies, or rheumatoid arthritis get out of control, there’s usually something wrong with the t-regs.

And according to a study that debuted in the journal Immunity earlier this week, a transcription factor called AIRE is behind T-regs’ peaceful behavior. 

When researchers at University of Chicago, broke lab mice’s ability to produce AIRE, the cells-that-would’ve-normally-become-tolerant-T-regs became aggressive instigators of autoimmune attacks. 

Which suggests that bringing balance to the transcription-factor force may be an excellent way to treat autoimmune diseases.

 

#5: Explain why some people with allegedly harmful mutations don’t get sick.

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One of the most ambitious transcription factor genetics projects of all is based out of Martha Bulyk’s lab at Harvard Medical School.  Last month, they published the first attempt to survey the diversity of mutant transcription factors in human genomes.

What they found may shock the biology grad students.

“We thought that this [variation in transcription factors] would be very rare, if it were found at all, in populations outside of rare disease families,” said Bulyk.

Since transcription factors are proteins, their existence depends on a DNA template, and transcription-factor-coding DNA is just as likely to develop mutations as any other gene.  Most geneticists have more or less assumed that breaking a transcription factor would be very bad for an organism, because losing a transcription factor means several other genes will probably get thrown out of whack.

But when Bulyk and the grad students in her lab–led by Luis Barrera– analyzed data from the Icelandic deCODE project, [Correction: The scope of their data was actually much broader, including data from The 1000 Genomes Project, The Exome Sequencing Project, and the Exome Aggregation Consortium, for a total of over 64,000 human genomes in their analysis.]  They found that many people were living with mutant transcription factors. Not only that, but many of those people didn’t show any signs of illness. 

The deCODE project sequenced the complete genomes of 2,636 Icelanders and gathered partial genomes from tens of thousands more. It’s the largest population-level genome-data-gathering project to date. Almost 1 in 10 of the Icelanders studied (7.7%) had a “complete loss of function” mutation that would most likely completely break one of their genes.

And Bulyk’s team found that a lot of those non-disease-causing mutations were in transcription factors. [Correction: Their analysis had two parts: One where they combed through the other data sets and identified which transcription factors had the most mutant versions– as opposed to trancription factors that would be identical across 64,000 people. In the second part of their analysis, they compared their list of frequently-mutated transcription factors to the genes where the deCODE study identified a complete loss of function. The transcription factors for which we found a larger number of damaging variants among 1kGP, ESP, and ExAC individuals, are more likely to be in TFs that are loss-of-function-tolerant,” Bulyk wrote in an email. Basically, mutations that change transcription factors’ ability to bind their target DNA pattern, seem to be pretty survive-able in some transcription factors. People with mutations in the most frequently-altered transcription factors were healthy enough to give informed consent and DNA samples. Which suggests that walking around with a gene expression mutation may not be super-unusual.

Of course,  it’s possible that some of the Icelanders were sick but undiagnosed or that others might have slight symptoms that are a bit too mild to register as disease. “Or maybe they just somehow contribute to making us different without being a disease,” Bullyk added.

Some transcription factors are not-negotiable. They have to be able to bind to a specific DNA sequence or else all hell breaks loose in a tissue.  “There were these mutations known to cause human disease that land in transcription factors and impair their ability to recognize their target sites,” Bulyk said.

But other mutations may simply make transcription factors less efficient at the job. Or they may slightly alter the TF’s target, transforming a “CATGATTAT”-seeker into a “CATGATTTT”-seeker.  A third possibility is that since transcription factors have overlapping jurisdictions–as in, many genes can be manipulated by several different TFs–one of the others may be picking up the slack.

Bottom-line: Mutations in transcription factors and the DNA base pairs where they like to land are common enough that every single human alive probably has their own, unique pattern of transcription factor behavior. 

The fact that we all use our genes differently— even when compared to people with identical genes– isn’t breaking news to epigeneticists. But it does complicate attempts to predict disease based on genome sequence alone.

“A lot of people are starting to go out and get their genomes sequenced. And there are some studies where they’re finding undiagnosed diseases. And while the cost of genome sequencing has gone down, what remains a significant challenge now is genome interpretation,” said Bulyk (in a  possible contender for “Scientist Understatement of the Decade”).

“It’s not as if you get a mutation and it either had no effect-meaning, it’s neutral– or there’s a complete loss of function.” she added. “There’s a wide spectrum of effects. Some are very subtle; some are very dramatic.”

 In other words, genes are far from destiny. They’re part of a system with thousands of checks and counterbalances. TFs are just one class of genetic balancer.

**tl;dr:**

Your cells are teaming with little proteins that can bind to DNA and  control how you use your genetic blueprints.

They’re called transcription factors and are pretty awesome.

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