This month, Prof. Franklin Pugh, molecular biology and genetics, and researchers Chitvan Mittal grad, Olivia Lang grad, and William K.M. Lai grad, found that inducible systems work in conjunction with constitutive systems to produce variable outputs depending on the “on” or “off” state of certain cofactors — this highlights new understandings of how the epigenome impacts transcription within cells.
The team published their study “An Integrate SAGA and TFID PIC Assembly Pathway Selective For Poised and Induced Promoters” in the journal Genes and Development.
The study used yeast as a model to ascertain the functionality of inducible systems within the genome dedicated to gene expression. Inducible systems are systems that are typically turned on by environmental changes in the microenvironment. Pugh likened yeast as a simpler model to study the molecular machinery that regulates genes in humans.
“Turns out that the molecular machinery that regulates genes in yeast is quite similar to the ones in humans, so by studying yeast at the molecular level, we get a better understanding of human gene regulation at the molecular level,” Pugh said. “But yeast is not human, so there are also many differences. The fundamentals are quite similar.”
With this yeast model, the researchers were able to define distinct mechanistic differences between types of inducible systems as compared to constitutive systems.
While inducible genes are genes that are only expressed under specific environmental conditions, constitutive genes are genes that are always expressed and serve as a background for the functioning of the genome’s gene expression.
Within the subgroup of inducible genes are promoters specific to these types of systems that have to be engaged or “induced” to effectively turn on the instructions for the gene.
The researchers distinguished five pronounced classes of promoters specific to their research goals in their paper: RP, induced, poised, constitutive and condition-specific, such as being induced by heat shock.
Through complex characterizations of these different types of promoters the researchers determined a dependency between specific cofactors, or general transcription factors, and inducible promoters.
A cofactor is a molecule attached to a protein that allows it to function. A transcription factor — a protein that participates in transcribing DNA into RNA — uses cofactors to transcribe DNA. Transcription is vital for the expression of a protein in a cell, which determines how a cell functions.
The researchers elucidated a dependency of inducible promoters on a high concentration of general transcription factors to a more specific factor associated with TBP — called TBP-associated factors or TAF.
This dependency suggests a compelling mechanism that could uptake TAF to create an environment capable of assembling the necessary supplies to begin transcribing DNA into RNA, but this warrants additional follow-up, according to researchers.
“We would like to try to remove TAFs in other ways [mutations] to achieve this and see if we can get at least some transcription,” Pugh said.
Although this complex communication and receptiveness throughout the epigenome of yeast and humans can never be fully assessed in one paper, Pugh points towards new directions of research from this novel paper with a quickly changing horizon.
“What we found is that most PIC [pre-initiation complex] components like TFIIB, TBP [and] RNA polymerase II do not [contact or interact with specific transcription factors],” Pugh said. “However, we found one that does: TFIIA. While TFIIA is thought to be a general transcription factor, it behaves more like a TAF.”
Pugh said these findings will further our understanding of how small environmental changes can impact our epigenome, opening further discussion into genetic disorders and other diseases that arise throughout the life of a human.