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"Junk DNA" and the Molecular Basis of Cell Identity

An interesting research article was published in Nature this week [Wang, K. C., Y. W. Yang, et al. (2011). "A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression." Nature].

In the study, a fascinating new regulatory role is identified for long intergenic noncoding RNAs (lincRNAs). Once thought to be "junk," or functionless vestiges of once-protein-coding-genes which have, through the course of evolutionary history, mutated to a state of non-functionality, the research documents that these lincRNAs have an extremely important -- even crucial -- role with respect to the determination of cellular identity. That is to say, lincRNAs play a critical role in determining the set of gene products which will be expressed in each respective cell type.

embryo.jpg

One particular biological phenomenon, which has always held an air of fascination for me, is the remarkable process of cell-type specification and differentiation which occurs during embryogenesis. While there is an element of intrinsic elegance in just about every network of gene expression, the process of embryogenesis has to be considered the pinnacle. In the present study, the researchers (Wang et al.) investigate the molecular basis behind the ability of fibroblasts to determine the local identity of skin cells and maintain the characteristic pattern of gene expression over scores of cell divisions.

The authors note in the abstract that,

Here we identify HOTTIP, a lincRNA transcribed from the 5′ tip of the HOXA locus that coordinates the activation of several 5′ HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.

The acronym, HOTTIP, the authors later note, stands for "HOXA transcript at the distal tip." In contrast to the previously identified HOTAIR (discovered by the same group) which acts as a silencer of gene expression, the newly identified lincRNA HOTTIP acts to organise chromatin domains (that is, the topology of nuclear DNA architecture) to coordinate the activation of gene expression.

So, how do these lincRNAs work to co-ordinate the maintenance of differential gene expression? Well, in the case of the newly-identified HOTTIP, the lincRNA (after contorting into its stem-loop structure) binds to an adaptor protein called WDR5, a component of the mixed lineage leukemia (MLL) complex which methylates lysine 4 of histone H3. This allows the HOTTIP RNA to activate its target Hox genes.

Why am I flagging this up, and what is its interest to those who follow the ID/evolution debate? First of all, there is the obvious point regarding hitherto-thought-to-be "junk RNA" or "genomic noise," which has now turned out not to be junk at all, but in fact be of crucial importance to the process of cell identity specification and development.

I have also long suspected that methylation patterns are not, principally, the key determinant of gene activation or silencing. Indeed, in the journal Genes and Development, Adrian Bird (2002) suggests that "DNA methylation may only affect genes that are already silenced by other mechanisms in the embryo." Rather, DNA methylation seems aptly adapted for a specific cellular memory function during development.

Obviously, the DNA sequence in every one of an animal's cells (with the obvious exception of T and B cells) is the same, and this includes their respective complement of Hox genes (which are, in large measure, responsible for determining the anterior-posterior segmentation of organisms during embryogenesis). Mutations in these Hox genes, if you recall, cause a body part to develop in an abnormal location during embryogenesis. In Drosophila, for example, mutations in the Antennapedia gene can cause the embryo to sprout legs from its head in place of antennae; mutations in the Ultrabithorax gene can cause the embryo to sprout the second pair of wings in place of the balancers that normally stabilise the insect in flight. Now, here's the thing. If the DNA sequence is the same in each respective cell type, how can DNA alone be the sole determinant of cell-type specification by virtue of differential gene expression? It seems fairly clear to me that the information specifying the overall body plan, or blueprint, of an organism, must lie -- at least in some measure -- beyond the remit of the DNA sequence. It seems that this is the only feasible way to resolve the spatial-specificity paradox (after all, regulation of gene expression presupposes -- it does not determine -- a pre-defined spatial co-ordinate system). Therefore, I am personally heavily inclined towards the view that Hox genes are turned on and off in respective cell types by a regulatory network which interacts with a pre-specified spatial co-ordinate system.

And if DNA is not the sole -- and perhaps not even the principle -- determinant of organismal morphology, then where does that leave Darwinism?