Tag Archives: hAT-Charlie

On Transposable Elements and Regulatory Evolution

Transposable elements (TEs), generally considered molecular parasites on the genome, are increasingly being linked to the evolution of new biological functions. TEs have been shown to be a source of novel genes and exons, the ‘arms race’ between them and their hosts has been a driving force in the evolution of epigenetic silencing mechanisms, and they have been shown to serve as cis-acting regulatory elements for host genes. This last role, as regulatory elements has potentially wide ramifications: TE mobilisation could cause changes to the expression of co-regulated suites of genes. Recently, the emergence of novel TEs and their mobilisation has been argued to be a causative factor underlying such ‘punctuated equilibria’ evolutionary phenomena as the Cambrian explosion and the rapid speciation of cichlid fishes. Two new papers analysing mammalian genomic evolution further link transposable elements with the spread of regulatory elements through the genome, and the evolution of novel characters.

CTCF binding sites.

CTCF (CCCTC-binding factor) is a DNA-binding protein with such a diverse and exciting array of potential roles attributed to it that it has been called a ‘master weaver of the genome’. It acts as an insulator, dividing different chromatin domains, and is therefore important for transcriptional activation and repression. This role appears to be linked to the formation of long distance chromosomal loops, and hence to the global organisation of the chromosomes within the nucleus. Schmidt et al. used ChIP-seq to define all the CTCF binding events in liver cells from five eutherian mammals (human, macaque, mouse, rat, and dog) and a marsupial (opossum). Using this data they defined a core DNA sequence motif that CTCF commonly binds, as well as sets of CTCF binding events that are conserved between the various species. In some lineages certain CTCF bound DNA sequence motifs were overrepresented. These overrepresented ‘motif-words’ were often embedded within lineage specific SINE repeats (short interspersed nuclear elements, non-autonomous non-LTR retrotransposons). For instance, mice and rats share about 2000 CTCF binding events that are associated with B2 SINES, mice have a further 5,300 B2 associated binding events and rats a further 1,200. Enrichments of CTCF binding events associated with lineage specific SINEs also occurred in the canine and opossum genomes (on a lesser scale). Surprisingly however, no similar TE associated enrichment occurred in the primate lineage. Looking at CTCF binding events that were conserved between multiple mammals, Schmidt et al. were also able to find over 100 binding events that were associated with fossilised ancestral transposable sequences.

Overall, this data shows that CTCF binding has expanded via retrotransposition in multiple mammalian lineages and that this is an ancient mechanism of regulatory evolution. CTCF binds a long DNA sequence motif (33/34bp) that is less likely to be generated by random point mutations than the smaller motifs more commonly bound by transcription factors. This is one reason why CTCF binding site expansion should be more associated with TEs than other regulatory sequence motifs. Another suggestion that the authors make to explain this association is that CTCF binding may protect TEs from repressive DNA or chromatin modifications.

Transposons and the evolution of pregnancy

During mammalian pregnancy, endometrial stromal cells (ESCs) differentiate in response to progesterone and signalling via the cAMP second messenger pathway, to produce a vascularised placenta that can accommodate implantation (a process termed decidualisation). The enhancer that drives expression of Prolactin in response to progesterone/cAMP signalling in ESCs is derived from a MER20 transposon (a hAT-Charlie family DNA transposon). Lynch et al. have found a strong association between MER20 elements and genes that are differentially expressed in mammalian ESCs and genes that are responsive to progesterone/cAMP signalling.

Analysing MER20s that are located close to stromally regulated genes, they found that, based on their association with CpG islands and various histone modifications, they often had regulatory potential. They then tested whether 21 randomly chosen MER20s bound various transcription factors and insulator proteins. 14 MER20s bound a suite of 5 different insulator proteins (including CTCF), whilst 5 different transcription factors important for ESC development bound together in 4 cases. This suggested that MER20s could be classified into ‘insulator’ and ‘enhancer-repressor’ types. Using a reporter gene assay in various cell types, they then showed that the majority of these MER20s acted as regulatory elements in response to progesterone/cAMP signalling specifically in ESCs.

This data indicates that the rewiring of the gene regulatory network of ESCs during the evolution of pregnancy was partly mediated by MER20 transposition events. In this case, MER20s contain sequences for regulatory assemblies of transcription factors responsive to specific signalling pathways, and hence have acted as cell type specific regulatory elements.

These two papers, as well as an increasing number of other studies, show that TEs are important agents of gene regulatory network evolution. The findings of Lynch et al. especially confirm the perspicacity of the discoverer of transposable elements, Barbara McClintock in terming them ‘controlling elements’.

See also: Retrotransposons as regulatory elements

Lynch, V., Leclerc, R., May, G., & Wagner, G. (2011). Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals Nature Genetics, 43 (11), 1154-1159 DOI: 10.1038/ng.917

Schmidt, D., Schwalie, P., Wilson, M., Ballester, B., Gonçalves, A., Kutter, C., Brown, G., Marshall, A., Flicek, P., & Odom, D. (2012). Waves of Retrotransposon Expansion Remodel Genome Organization and CTCF Binding in Multiple Mammalian Lineages Cell, 148 (1-2), 335-348 DOI: 10.1016/j.cell.2011.11.058

Zeh, D., Zeh, J., & Ishida, Y. (2009). Transposable elements and an epigenetic basis for punctuated equilibria BioEssays, 31 (7), 715-726 DOI: 10.1002/bies.200900026

Phillips, J., & Corces, V. (2009). CTCF: Master Weaver of the Genome Cell, 137 (7), 1194-1211 DOI: 10.1016/j.cell.2009.06.001