Brian J. Abraham, Pre-Doctoral IRTA Fellow, Graduate Student
National Heart, Lung and Blood Institute, National Institutes of Health, Boston University
All cell types, from skin cells to blood cells, come from stem cells, and so these diverse cell types all contain the same set of DNA letters and genes. Despite this similarity they can have very different functions. This differing functionality is accomplished in part by the fact that certain genes are “turned on” in some cell types and “turned off” in others.
My first goal is to figure out which genes are transcribed from DNA into mRNA (i.e. “turned on”) in which cell types. My second job is to figure out what determines whether or not these genes are transcribed.
One way the transcription of genes is controlled is through the packaging of the DNA in the nucleus. To fit the 3 meters of DNA into the nucleus, the genome is wrapped around protein spools called nucleosomes. The more highly condensed a gene is, the harder it is to transcribe. Where these nucleosomes are located, and how they are spaced on the DNA, as well as which chemical modifications they have can also make transcription easier or harder. Some of these chemical modifications act as flags to recruit other proteins to eject, incorporate, and/or shift nucleosomes, or to directly control the transcription machinery.
Understanding the packaging-mediated regulation of gene transcription will help us uncover the biology behind what makes blood cells different from skin cells.
I’m a computational biologist, so I work at a computer screen all day. This means I have to bring a lot of imagination to figure out what a big set of numbers from a large-scale sequencing experiment or multi-gene analysis really means. I write programs of my own, create statistical analyses, and use others’ software to turn large sets of numbers into meaningful lists and figures, so that I can draw biological conclusions from mathematical data points. These data points are usually from sequencing experiments that interrogate the whole genome for gene expression or for where proteins, e.g. nucleosomes, bind.
The building blocks of nucleosomes, histone proteins, may differ allowing nucleosomes to perform different functions. These histones can be chemically modified, and these modifications alter the characteristics of the nucleosome. Certain types of nucleosomes are found on genes that aren’t transcribed, i.e. “turned off.” Strangely, most genes remain “turned off” after these “turning off” nucleosomes are lost, meaning there are other factors that keep the genes turned off after the initial ”turning off”.
Even before a decision is made by a stem cell to become a mature cell, genes that are important for that cell type are prepared by using both “turning on” and “turning off” histones. When the stem cell begins to decide what it will become, one type of histone leaves, leading to transcription or silencing of the gene. This is especially important in immune system-related genes, where specific genes need to activate to respond to a specific pathogen and many signals are heeded.
We still need to find what makes different flavors of nucleosomes target particular genes at particular times. We’re still not sure exactly how or to what degree nucleosome patterns are inherited by dividing cells, let alone scaled up to inheritance between parent and child. Next, what happens biochemically to bring about the “on” or “off” state of the gene bound by the flavored nucleosome? This preparation of genes with both “on” and “off” signals also needs to be clarified, as it seems not all important genes have both marks in stem cells.