August 11, 2016

Transcription factor evolution

Vanderbilt researchers have discovered a novel model of evolution for factors that control gene expression.

by Sanjay Mishra

Transcription factors are proteins that control gene expression by binding to specific DNA sequences.

In a paper published recently in the journal Cell Reports, Soumya Ganguly, Ph.D., Jens Meiler, Ph.D., Heather Darling, and colleagues at Yale University provide a novel model of transcription factor evolution in which subtle genetic changes dramatically alter the functional output of a developmentally important protein complex.

The researchers studied molecular mechanisms underlying a functional interaction between two transcription factors: HOXA11, involved in development of limbs, kidneys and reproductive organs, and FOXO1, which plays important roles in glucose and lipid metabolism.

They describe how mutations, a few amino acid substitutions, “disorder” a region of HOXA11 and fundamentally change its interaction with FOXO1, creating a “neo-allosteric bridge” between the two transcription factors.

This, in turn, unmasks HOXA11’s “activation domain,” which regulates gene expression in the uterus of placental mammals, including humans. In primitive mammals, this gene expression is repressed and the FOXO1:HOXA11 interaction does not release it.

This research was supported by grants from the John Templeton Fund (grants #12793, 54860).

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