#gene switch

We have discussed the way genes regulate our earliest development and described the way that master switches turning genes on and off are functioning at critical junctions in decision points about what a given cell will become.  Remember that while all of our cells have the same DNA and the same genes not all of the genes are active or turned on and the active genes are different from cell type to cell type.  We now know that the type of cell is determined by which of these genes are active and which are inactive.  An active gene is one that is “expressed”, that is a gene that produces RNA.  The RNA (except for specialized RNAs that have their own regulatory functions) is sent out of the nucleus and used to pattern a protein.  The proteins define the cell type and function.  We talked about a kind of decision tree in which an active gene sends a cell down a given pathway and prepares it for the next decision branch until the final state or “fate” of the cell is determined.

But what makes the gene active?  How does the cell decide what genes will be turned on and what genes will be turned off? Previously we described a key element of this process, proteins known as transcription factors.  These proteins have the remarkable ability to recognize certain sequences of the four “letters” of the genetic code in our DNA. These recognizable sequences occur near the gene in the DNA.  The transcription factor sticks to the recognition sequences in a protein –DNA interaction.  This sets in motion a cascade of interactions between proteins that result in the assembly of the machinery that will produce the RNA that defines the protein.

Is that all there is to it? Of course not.  Remember that we discussed how while the gene is a linear sequence of A.T, C, and Gs that are the basic letters of the DNA code the DNA is itself enmeshed in proteins in a highly ordered and specific way that helps pack 3 billion “letters” that make a chain of DNA meters long fit into a nucleus that is about .0001 inches in diameter!   We now know that the proteins that accomplish this also have the remarkable ability to regulate whether or not a gene is turned on or expressed. The proteins and DNA are interacting to make this happen and are collectively referred to as chromatin. The state of the chromatin can be conducive to the active expression (RNA production) of a gene or inhibitory of expression in a so-called repressive state.  There is an amazing degree of specificity to this regulation that defines what genes in which cells at what time are ready and able to be expressed. For the most part the proteins that accomplish this are the same through the entire DNA system of genetic code (known as the “genome”) but the combinations of these proteins confer an amazing degree of specificity to the process.

 The 3 meters of DNA in our cells is coiled tightly to pack into a chromosome or into the nucleus.  Part of the coiling is from winding around “nucleosomes”, the small blue balls above somewhat reminiscent of “spoolies” the rage hair curlers of the 1960′s.  The chromatin image from http://study.com/academy/lesson/nucleosome-definition-structure-quiz.html

The proteins that make up the chromatin include histones that create small barrel shaped structures that DNA winds itself around.  The histone and DNA are known as nucleosomes and they are reminiscent of the 1960’s rage, spoolies!  There are four histones in each spoolie and very remarkably the histones have protein “tails” that literally stick out from the structure.  Those tails in turn have the ability to alter their chemical composition at the hands of protein enzymes whose job it is to make the alterations. These chemical modifications in turn alter the ability of other proteins that actually create the RNA to come together at the beginning of the gene to start making RNA.  The proteins that make these modifications can be “writers”, “erasers” or “readers” and function much as their names imply.  The combination of these proteins and the modification to the tails define the chromatin state.  The chromatin state is what is modified as genes activate to expression or deactivate to repression.  Normal development is a delicate balance between cell division and cell differentiation, which is established through the time of the pregnancy to successfully complete the decision tree of gene expression.  This four dimensional problem is solved by creating astronomically large numbers of combinations of proteins.

 A gene switch! Notice the spoolie has little tails with chemicals that connect it to other proteins that operate the switch.  How cool!  From Petell, et al., 2016

The protein enzymes that alter chromatin are said to “remodel” the chromatin and without that process we could not develop normally.  Indeed just a few examples of what happens when this remodeling process is messed up should convince us of the central role chromatin plays in our health. 

We have talked about how simple organisms that are not like us still teach us very relevant lessons about our lives.  Yeast is a great example, many basic processes have been discovered using them.  A gene called switch was discovered in yeast and then an equivalent gene in humans was subsequently discovered.   This gene codes for a protein that makes modifications to the chromatin. In fact there is a family of these proteins that function in the same way in different contexts. When these genes are broken in human beings the result is cancer.  A wide range of terrible human malignancies result from mistakes in the genes. In the case of mistakes in a gene called SMARCA5 patients may develop Ewing’s sarcoma. This is a terrible tumor of the bone that primarily affects children; modern treatment thankfully can save half of these kids. 

The proteins of the gene switches are assembled into “transcription factories” in the cell’s nucleus. Machines like Top2 below are in there and together they remodel the chromatin landscape and recruit other machines to make the RNA.

A representation of the chemical structure of Top2 (a topoisomerase).  The golden spiral at the top represents DNA winding through the protein.  It is almost like a nutcracker! It modifies chromatin and regulates the expression of genes. Image from Wikipedia.

DNA is wound up pretty tightly.  This makes moving important protein machinery needed to create RNA into the gene difficult. Proteins called topoisomerases work to change that winding during regulation of gene expression.  One, known as Top2B, is very important in modifying the chromatin landscape or the “topology” of the gene during regulation of gene expression.  When mutations occur in the gene that codes for Top2B the result can be colon cancer or leukemia.

One final example of the importance of chromatin remodeling in regulation of gene expression is a protein called RBBP4.  This protein is very important in changing the chemical tails of histones that we discussed above.  In fact it operates both as a histone writer and a histone eraser and results gene repression.  When mistakes occur in the gene coding for this protein the result is a devastating childhood cancer of the eye called retinoblastoma.

As we develop starting as a single cell, the fertilized egg, we become trillions of cells with thousands of functions arrayed into more than 200 tissues.  Each of the cells mostly has the same DNA and the process of turning genes on and off is what makes a cell achieve its ultimate fate, what make cells different from each other, in other words what drives differentiation.  Key to that process is the landscape or topology of proteins that the DNA lies in and a constant process of modification of that landscape creates an amazingly dynamic and robust control mechanism for coordinating gene action that results in all of the cells that make us up.  So remodeling, important in so many aspects of our lives is also critical to giving us life!

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