LTP-related genes are clustered in genome

LTP activated genes are clustered on chromosomes -- or so says some work by Park et al in JBC.

LTP -- or long-term potentiation -- is a process by which synaptic strength -- the ability of one neuron to talk to the next neuron -- is increased by activity. It involves the combination of several processes with different time courses, but some of the best characterized aspects of LTP are genes who transcription is activated by a protein called CREB. CREB is activated during LTP, and CREB activated genes are go on to consolidate LTP at the activated synapse.

There are temporally distinguished forms of LTP that require distinct mechanisms for their
maintenance (8,9). One is the short-term LTP (early LTP) that usually lasts for less than one hour and is resulted from modifications of preexisting synaptic proteins. Another is the longerlasting LTP (late LTP) that requires activityinduced protein synthesis and gene transcription (8). At the cellular level, the maintenance of late
LTP is associated with structural remodeling of synapses which can lock-in the change of synaptic
strength (8-10). Activity-induced protein synthesis and gene expression are probably necessary to support such longer-lasting structural changes of the synapse. Therefore, identifying genes that are regulated during LTP is essential for understanding the molecular mechanism underlying long-lasting LTP.

What is weird about this work is that they show that the genes activated by LTP and by CREB are clustered on chromosomes. There is really no reason for this to be the case. The only other example I have heard about where the physical location of genes was related to their function is Hox genes -- genes involved in developmental patterning -- and that is because all of the genes are very closely related. In this case, you have totally unrelated genes being clustered on chromosomes because they are functionally similar -- not structurally similar.

A long quote where the authors speculate about why this might be is below the fold (incidentally ARGs = activity-related genes):

Chromosomal clustering and transcriptional regulation of ARGs - One striking finding from this study is the chromosomal clustering of ARGs. Previous studies indicated that genes co-expressing in the same tissue tend to cluster at chromosomal domains (34,75-77), but the biological significance of gene clustering was not clear. In prokaryotes, genes involved in the same biochemical pathway are often organized into operons, in which the clustered members are co-regulated by the same promoter (78). Similar organizations of functionally related genes are not found in higher organisms except C. elegans (79), although rare clusters of homologous genes that arose by duplication and divergence (e.g. the beta-globin and Hox gene clusters) do exist (80). On the other hand, the lack of operon-like structures in mammals does not preclude the possibility of a structured genomic organization related to biological functions. We found clustered ARGs are functionally correlated in LTP regulation, although they apparently do not share the same molecular functions. Furthermore, previously identified LTP-related genes are also clustered on chromosomes and associated with ARG clusters. These findings indicate that genes which respond to synaptic activities and functionally correlated in synaptic plasticity are clustered in the genome. As suggested by the chromosomal clustering of ARG homologs and the conservation of ARG clusters in different genomes, there is a selection pressure to maintain these gene organizations during evolution. Together, these lines of evidence strongly argue for a biological relevance of ARG clustering. Interestingly, memory consolidation genes were reported to concentrate on specific chromosomes (20).

What is the functional significance of chromosomal ARG clustering for LTP-related transcriptional regulation? One possibility is that clustering of ARGs facilitates transcriptional coordination of the functionally related genes during LTP. Because LTP induction regulates the expression of numerous ARGs, the coordinated expression of ARGs is likely critical for LTP. For instance, the expression of some ARGs involved in the same molecular process of LTP may need to be temporally coordinated, while the level of certain ARG products that interact may need to be coordinated in a stoichiometric manner. Clustering of ARGs on chromosome may provide a genomic platform for the coordination of ARG transcription during LTP. We propose that chromosomal clustering may facilitate coordinated transcription of different ARGs from the following aspects. Firstly, clustering provides a mechanism to reduce the burden of unpacking of DNA by decreasing the number of chromatin loci that need to be 'opened' for transcription of ARGs during LTP. Given the extensive DNA compaction in the nucleus and the large number of LTP-related ARGs, such a strategy for simplifying DNA unpacking is probably important. Secondly, recent studies indicated that active genes in chromatin loops are dynamically organized into the transcription factories in the nucleus (81,82). Compared to a dispersed distribution, clustering of functionally related ARGs on chromosomes would dramatically facilitate the formation of such transcriptional organization. In fact, given the large number of ARGs regulated by LTP induction, such a chromosomal compartmentalization of ARGs is likely necessary to avoid the package of numerous chromatin loops in transcription factories. Thirdly, an 'open' chromatin loop usually contains multiple genes that are potentiated for transcription. If there is only one ARG in an 'open' chromatin loop, other potentiated genes may not relevant to LTP. Even if the expression of these irrelevant genes is not harmful for LTP expression, it would be a waste to transcribe them. From this viewpoint, clustering of ARGs in chromatin domains may provide a genomic mechanism to reduce non-specific transcription from genes that are irrelevant to LTP. (Emphasis mine.)

Furthermore, the clustering is relatively conserved in mammalian evolution. Here is a chart showing the conservation of the gene clusters from rat to human but not in Drosophila and C. Elegans (click to enlarge):

Caption:

Clustering of ARG homologs and conservation of mouse ARG clusters as syntenic regions in other genomes. A. Clustering analysis of mouse ARGs and their homologs in other genomes. ARGs and their homologs are significantly (p<0.05) clustered in mouse and other genomes. IGD: intergenic distance. B. A schematic diagram showing the ARGs clusters on the mouse chromosome 2 (upper panel) and the maintenance of these clusters in syntenic regions of the human genome (lower panel). Individual ARG clusters are labeled with letters (A to V); ARG clusters on different human chromosomes are indicated by various colors and numbers (lower panel); Reversed ARG clusters are indicated by arrows. C. Conservation rates of mouse ARG clusters in the human, rat, Drosophila and C. elegans genomes. The percentage of mouse ARG clusters maintained in other genomes was calculated. Only clustered mouse ARGs that had identifiable homologs in other genomes were used for this analysis. A mouse ARG cluster was considered conserved in another genome if 75% of the ARGs in the mouse cluster were found at the same chromosomal locus in the same topographic order.

Hat-tip: Faculty of 1000.