Structural Biochemistry/Attributing functions to genes and gene products

Introduction

The central dogma for the expression of physical traits, though important, lacks a level of depth desired for by modern bio-chemists/physics and biologists. It is not enough for modern scientists to know that proteins are translated from RNA and RNA is transcribed from DNA. Rather, modern scientists in biological research work to know the depth in which some function or trait can be attributed to the specific structure of DNA, especially as it involves specific genes.

Gene Centrality and RNA

The central dogma of gene expression came to light over 50 years ago, and since then there have been further advances into the specifics of how DNA is expressed biochemically. We are not limited now to the simplistic dogma, DNA -> RNA -> Protein, due in part to our knowledge of other types of RNA, broken up into different categories; RNA for translation and for regulation. Classical studies have classified mRNAs, rRNAs, and tRNAs as mostly being part of the translation machinery in gene expression, whereas small micro RNAs (miRNAs) serve as RNAs for regulation.

Mapping Function onto Structure

In this context, we will refer to "function" as a behavior mediated by the structure of the gene or DNA. The importance is in the scientific method for attributing function to a specific structure/gene.

Imagine that you have isolated a particular protein that allows detection of a particular catalytic activity. If you were to then react the particular protein with a given substrate and find that the particular catalytic activity was undergone, it would be seen as reasonable to credit the catalytic activity as a function of the particular protein, which we will call the "biochemical function". This is logical by deductive reasoning. (Note: In this first experiment this is all happening in isolation. This is not being tested in a real life biological scenario. It is happening in a chemistry lab). Now, if another researcher studies the function of the same particular protein by modifying the DNA sequence that encodes for the amino acid that forms your protein, the researcher could very well discover that changing the DNA in a given cell so that it encodes for the particular protein also changes other features of the cell. (Note: In this second condition the experiment takes place in a biological system). The subsequent attribution would then be that the altered features of the cell are caused by the gene change and the subsequent gene product (the particular protein that was encoded for). Because the gene was altered to produce the particular protein, it would also be assumed that the altered features of the cell were a function of the protein, which we can call the genetic function.

In the first case, we observe the isolated function of a protein with some substrate. The function was directly mediated by the protein, and nothing else. In the second case, we have see the function of the protein and its interactions in a cell, as well as the confounding variable that is the changed genetic sequence. The significance of these two cases is to show that the attribution of the function of a gene is dependent on the method it was studies. In the first case, the gene is studied indirectly by looking at the effect of the gene it encodes for. In the second case, we look at the effect of altering a genetic sequence so that it produces the particular protein, or in other words, the genetic sequence is changed to that which we wanted to study. These two cases follow different methods, and independently convey esoteric information. But viewed in conjunction, it can be be seen that the biochemical and genetic functional attributions are two factors on a continuum.

Noncoding RNAs

There is a large preponderance of long transcribed RNA transcripts that don't code for proteins. These are called long non-coding RNAs (lncRNAs). Though these RNAs do not code for proteins, they still have a large effect in the expression of genes, thus disrupting the simple genetic dogma. Emerging research shows lncRNAs use specific enzymatic activities in the genome by forming extensive networks of ribonucleoprotein (RNP) complexes with chromatin regulators, which can be used to target specific/appropriate locations in the genome. Thus, lncRNAs can be used as modular scaffolds, like a sort of regulatory RNA, affecting gene control, and by extension gene expression, by means of specifying organization in RNP complexes and chromatin states.

Guilt by Association: In determining the possible functions and ways of regulation of lncRNAs, a method was created for generating hypotheses for the function of lncRNAs by co-expression of lncRNAs with mRNAs (protein coding RNAs). By doing this, the lncRNAs can be grouped with pathways they may possibly regulate, according to their co-expression with the respective mRNAs. This is a correlative method, which is to say that what is being observed is whether there is statistical significance, and from this there are postulations as to the mechanisms for co-regulations and co-expression. Using this method, several families of lncRNA have been revealed by their association patterns (whether they do or do not associate) with different RNA expression pathways. For example, a specific lncRNA, termed lincRNA-p21 (one correlated to p53) was found to be directly regulated by p53, subsequently forming a lncRNA-RNP with a nuclear factor that acts as a global transcriptional repressor, all of which facilitates p53-mediated apoptosis. This is all to say that the lncRNA could serve a significant role, due to the given example in which it serves an important biological function (apoptosis).

References

Greenspan NS. "Attributing functions to genes and gene products." Trends Biochemical Sciences. 2011 Jun;36(6):293-7. <http://www.sciencedirect.com/science/article/pii/S0968000411000028>.

Rinn JL. Chang HY. "Genome Regulation by Long Noncoding RNAs." Annual Reviews. 2012 Jul;81:146-166. <http://www.annualreviews.org/doi/full/10.1146/annurev-biochem-051410-092902?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&>.