Previously, we mentioned there are sections of the DNA (called non-coding DNA) that do not lead to the production of a protein because they get cut out of the RNA before it leaves the nucleus of the cell. These sections of non-coding DNA are called introns.

But what is in the intron sequences and why are they there?

There is not a complete answer to that question but we know that they contain special sequences called enhancers that also bind regulatory proteins. Enhancer sequences are not just in intron regions though, these sequences can be almost anywhere in the DNA sequence in relation to the gene they regulate. This results in a fine modulation of the expression of the gene, not just on or off, but where and when the gene is on or off. This adds a whole new layer of complexity to our genetic coding.

By building combinations of these regulators acting on many genes a tremendous number of combinations of gene expression is possible and that is how differentiation occurs. It’s how we start as a single fertilized egg cell and become functioning sentient individuals with hundreds of tissues composed of trillions of cells.

Hormones are small proteins that can make things happen. This is where estrogen and testosterone come in. These steroid hormones will bond (stick to) special proteins called receptors. The receptors and hormones stick to each other because of structural features (shape) of each of them, resulting in them physically fitting together in a way that promotes the binding.

Once the hormone binds their respective receptors the protein complex moves in to the nucleus. It then finds a specific DNA enhancer sequence in target genes and sticks to it.

For example, the hormone estrogen binds to an estrogen receptor, like ER alpha or ER beta, and forms a hormone/receptor combination called a protein complex. This protein complex gets shuttled into the nucleus of the cell and finds the enhancer sequence of its target gene; for estrogen the enhancer is called the Estrogen Receptor Element (ERE). This association results in very subtle regulation of gene expression of the target gene. This is an exquisitely precise process requiring exact molecular concentrations and timing to work correctly.

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DNA packaging in the cell. Cytoplasm is pink and the nucelus is blue in the diagram of the cells. A dividing cell has replicated all of its DNA to make four copies of all the genes. The DNA double helix (bottom of the figure) is wound around little beads, proteins called histones, that limit access of transcription factors to the gene. The entire structure is densely coiled. The cell must package about two meters of DNA into a space about 10.5 meters across, and replication must faithfully copy three billion base pairs in about an hour. Remarkable!

From the Figure we can see that the DNA is tightly wound and coiled and is wrapped around proteins (represented as little balls in the picture) called histones. DNA wrapped around histone proteins like beads on a string are called nucleosomes. For the regulatory proteins, transcription factors, and the RNA polymerase to get to the DNA it must be unwrapped and opened up. The protein enzyme histone acetylase helps this process by neutralizing charges on the acyl groups of the histones thereby decreasing the ability of histones and DNA to stick (bind) to each other. This results in the DNA opening up and allowing transcription (expression) to occur. The expression of IGF-1 (Insulin growth factor-1) is regulated in part by steroid hormones (like estrogen) and in turn IGF-1 enhances histone acetylation thus impacting the availability of genes to transcription factors.

Enhancer sequences can be a long way from the gene they regulate in terms of linear sequence. In Figure 5 we can see that the DNA is coiled around and packed into the small space of the nucleus in a very complex way. In fact by following the coils around one can appreciate that distant regions in terms of the primary linear sequence may be very close in three-dimensional physical terms because the primary sequence may wander all around in space and wind up back at the gene. The ancient Greeks and Spartans would encode secret messages in a similar fashion (known as a Scytale cypher). They would wrap a belt around baton of a specific thickness such that letters that were spaces apart would lay next to one another on the baton, and reveal the “hidden” message.

Information is also present in specific chemical modifications of the genome. In aggregate these are called epigenetic marks or the epigenome. The marks include methylation of DNA, which is the addition of methyl groups to cytosine bases. In large numbers these epigenetic methylated cytosines will result in turning a gene off (inhibit transcription)thus altering the original genetic code. Epigenetic alteration of the histone proteins themselves also carries information.

Importantly, methylation patterns are heritable, thus alteration of epigenetic marks by for example endocrine disruptors in Mom will affect not only the offspring that suffered the exposure but that child’s child as well.

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

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Phil Iannaccone is a Professor of Pediatrics and Pathology at Northwestern University Feinberg School of Medicine.

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