Understanding the architectures of proteins and the machinery at genes

Researchers from Cornell University have discovered a crucial mechanism in how genes are controlled thanks to yeast, a small organism that is necessary for the production of beer and bread.

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Gene transcription, the complex process by which human cells read genetic information encoded in DNA, was previously thought to be activated only when certain regulatory factors went to specific DNA regions.

A group of Cornell researchers revealed that some genes have their transcription regulatory factors and cofactors already in place, but in a dormant condition. The research was published on October 27^th, 2022, in the Genes & Development journal. These “poised” genes become extremely active when given the right cues.

The scientists disassembled the yeast transcription machinery using CRISPR techniques to rigorously investigate how it controls gene expression. Since yeast and humans use essentially the same molecular machinery to control their genes, yeast serves as a good model for figuring out how people control their genes.

It’s like the game of Jenga, where you remove a wood block from a tower of blocks and see if the whole thing crashes down. That’s how we learn how protein machines work inside cells.”

B. Franklin Pugh, Greater Philadelphia Professor, Molecular Biology and Genetics, College of Arts and Sciences, Cornell University

Using information about how yeast genes are controlled, the researchers classified them into two classes. The first and biggest group performs fundamental housekeeping duties that enable the cells to survive and grow. Because the transcription machinery has trouble getting to each gene, these genes are always “on” at very low levels.

The “inducible” genes, on the other hand, have an entire entourage of proteins assembled nearby. When prompted by environmental cues, this poised entourage guides transcription machinery. As a result, there is a lot of induced transcription.

The value of being poised is that certain genes, like environmental response genes, can rapidly respond to a changing environment; for example, when yeast encounters and metabolizes bread sugars, causing the bread dough to rise.”

B. Franklin Pugh, Greater Philadelphia Professor, Molecular Biology and Genetics, College of Arts and Sciences, Cornell University

Similar metabolic processes take place in human cells after food intake.

Pugh has been studying gene control for over 30 years. As a Cornell student, he was fascinated by the idea of how human genes are regulated—so important to biology yet so mysterious—and he has dedicated his life trying to comprehend it.

With this paper, we finally got to the core question of how do these gene-specific transcription factors that are sensing the environment recruit the core transcription machinery. We could not completely answer the question in this paper, but we got solid insight into how that process works.”

B. Franklin Pugh, Greater Philadelphia Professor, Molecular Biology and Genetics, College of Arts and Sciences, Cornell University

Pugh previously mapped the exact binding locations of over 400 different chromosomal proteins in the yeast genome, the majority of which control gene expression.

Pugh adds, “That paper shed significant light on understanding how all these proteins come together and work together to read and regulate genes.”

The current study is based on the earlier work, diving deeper into comprehending the architectures of proteins and the machinery at genes.

“Building upon years of existing research and combining them with modern and elegant genomics tools helped us in filling gaps in the current knowledge as well as in making new discoveries,” says first author Chitvan Mittal, research associate at the Baker Institute for Animal Health in the College of Veterinary Medicine.