GTF2IRD2 from the Williams-Beuren critical region encodes a mobile-element-derived fusion protein that antagonizes the action of its related family members.
GTF2IRD2 belongs to a family of transcriptional regulators (including TFII-I and GTF2IRD1) that are responsible for many of the key features of Williams-Beuren syndrome (WBS). Sequence evidence suggests that GTF2IRD2 arose in eutherian mammals by duplication and divergence from the gene encoding TFII-I. However, in GTF2IRD2, most of the C-terminal domain has been lost and replaced by the domesticated remnant of an in-frame hAT-transposon mobile element. In this first experimental analysis of function, we show that transgenic expression of each of the three family members in skeletal muscle causes significant fiber type shifts, but the GTF2IRD2 protein causes an extreme shift in the opposite direction to the two other family members. Mating of GTF2IRD1 and GTF2IRD2 mice restores the fiber type balance, indicating an antagonistic relationship between these two paralogs. In cells, GTF2IRD2 localizes to cytoplasmic microtubules and discrete speckles in the nuclear periphery. We show that it can interact directly with TFII-Iβ and GTF2IRD1, and upon co-transfection changes the normal distribution of these two proteins into a punctate nuclear pattern typical of GTF2IRD2. These data suggest that GTF2IRD2 has evolved as a regulator of GTF2IRD1 and TFII-I; inhibiting their function by direct interaction and sequestration into inactive nuclear zones.
Neuromuscular and Regenerative Medicine Unit, School of Medical Sciences, The University of New South Wales, Sydney 2052, Australia. s.palmer@unsw.edu.au
Stephen J
SJ
Palmer
Kylie M
KM
Taylor
Nicole
N
Santucci
Jocelyn
J
Widagdo
Yee-Ka Agnes
YK
Chan
Jen-Li
JL
Yeo
Merritt
M
Adams
Peter W
PW
Gunning
Edna C
EC
Hardeman
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002417:Cattle; D002467:Cell Nucleus; D002522:Chlorocebus aethiops; D019143:Evolution, Molecular; D006367:HeLa Cells; D006801:Humans; D020071:Interspersed Repetitive Sequences; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000378:metabolism*; D019473:Transcription Factors, TFII / Q000378:metabolism*; D018980:Williams Syndrome / Q000235:genetics*
C486330:Gtf2i protein, mouse; C486558:Gtf2ird1 protein, mouse; C525555:Gtf2ird2 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D019473:Transcription Factors, TFII