FlySox

Sox domain genes encode proteins related to the mammalian testis determining factor, SRY, and are part of a larger family of transcription factors with DNA binding domains related to the general chromatin protein HMG1.  The HMG-domain has interesting properties; it binds in the minor groove and induces a large bend in the DNA helix, prompting the suggestion that these proteins may have a chromatin architecture function. Many members of the family, such as HMG1, are abundant chromosomal proteins which bind DNA with little or no sequence specificity.  Others, such as the SOX’s and the mammalian lymphocyte transcription factor LEF1, have restricted tissue specificity and exhibit a moderate degree of sequence specificity.  We have been studying Sox genes in flies to try understand their biological functions and how they act at a molecular level.

 

We identified the first fly Sox gene when Peter Koopman sent us a PCR product back in the days when Sry had just been discovered.  It turns out that the gene corresponds to the Dichaete locus, identified by Bridges in 1914, and as such is probably the oldest known Sox mutation in any organism. Over the years we cloned several Drosophila SOX genes but our current focus is on the Group B Sox protein Dichaete and SoxNeuro, since they appear to have important and conserved roles in CNS specification.

We are also interested in Sox100B, a gene we have recently shown is required for testis development in flies. This is a remarkable finding since the mammalian orthologue of Sox100B, Sox9, is known to be required for testis development.

One intriguing aspect of Sox biology is their apparent “functional redundancy” (I prefer the term functional compensation since I don;t think evolution can sustain redundant genes).  In flies, as with every other higher metazoan studies to date, multiple group B Sox genes are co-expressed in the CNS, raising the question of what they do in cells where they are both present.  We are tackling this in a number of ways, comparing Dichaete and SoxN binding in the embryo and looking at the binding of each protein when the other is absent.  In addition, we are looking at both of the fly Group B Sox proteins in other Drosophila species to determine whether their binding profiles are conserve.

 We are currently using a combination of gene expression profiling and ChIP array to understand the set of Sox targets in the genome and make predictions about how they function.  We have published extensively on the genome biology of Dichaete and SoxN, mapping binding with a very stringent overlap between DamID and ChIP. More recently Enrico mapped Dichaete binding in SoxN mutant embryos and vice versa revealing unexpected complexity in the way these proteins appear to interact in the genome. Sarah took an evolutionary approach, comparing SoxB1 binding in different drosophila species, revealing that regions bound by both Dichaete and SoxN are more conserved than those binding either protein uniquely.
An exciting observation we have made is that when we compare genes bound by Dichaete and SoxN in the fly genome, we find a very high overlap with orthologus genes bound by Sox1 or Sox2 in mouse neural stem cells, indicating that the underlying regulatory networks controlled by SoxB1 genes in the CNS may be conserved. Currently, Josh is going beyond the fly and is building tools to look at SoxB1 binding in the red flour beetle Tribolium castaneum. We have previously found that the underlying genomic organisation of SoxB1 genes in the fly is very highly conserved in insects – an intriguing observation we are exploring.
More recently, in a collaboration with Alistair McGregor’s lab at Oxford Brooks, we have shown that the repertoire of Sox genes in conserved in the house spider Parasteatoda tepidariorum and that both SoxN and a Dichaete class gene appear to have conserved functions in CNS development and segmentation (Paese et al (2018) eLIFE)

Current Lab Members

Stefan Koestler

Previous Lab Members

Olimpia Bonpadre
Josh Maher
Sarah Carl
Enrico Ferrero
Jelena Aleksic
Samantha Loh
Carol McKimmie
Shreeya Nanda
Lisa Meadows
Nich Phochanukul
Paul Overton
Natalia Sanchez Soriano
Shih-Pei Shen
Alex Whitworth
Gertrud Woerful

Collaborators

Alistair McGregor

Mark van Doren