Being an Adult Cell Requires Constant Prompting

Preventing differentiated cells from regressing to a stem cell-like, precancerous form depends on the action of a group of enzymes called histone H3 lysine 4 (H3K4me) methyltransferases.

The H3K4me methyltransferases and their cofactors are essential for embryonic development and the establishment of gene expression patterns in a cell-specific and heritable manner. To examine their role in maintaining correct gene expression in adult cells investigators at the University of Michigan (Ann Arbor, USA) genetically engineered a line of mice whose heart cells were susceptible to the inducible inhibition of PAX interacting (with transcription-activation domain) protein 1 (PTIP), a key component of the H3K4me complex.

They reported in the July 1, 2011, issue of the Journal of Clinical Investigation that reducing H3K4me3 in differentiated heart cells was sufficient to alter gene expression profiles. One gene regulated by H3K4me3 was Kv channel-interacting protein 2 (Kcnip2), which regulates a cardiac repolarization current that is down-regulated in heart failure and functions to generate irregular heartbeats. The inhibition of this gene led to a decreased sodium current and action potential-upstroke velocity, and significantly prolonged action potential duration (APD). Treatment with isoproterenol and caffeine in this mouse model resulted in the generation of premature ventricular beats, an indicator of lethal ventricular arrhythmias.

“The results bring us one step closer to developing treatments for issues associated with aging or chronic diseases in which cells lose their ability to maintain a stable pattern of gene expression”, said senior author Dr. Gregory R. Dressler, professor of pathology research at the University of Michigan. “What we found was that it is important for the body to keep telling the heart cell, “You are a heart cell, you are a heart cell.” When you knock out a piece of those instructions, the heart cell starts to forget who it is. These changes start off small, but over time they can have big effects on the organism.”

“It is well known that human beings pass a life code, bound up in the double helix of our DNA, from one generation to the next. What is less well understood is that they also transmit sets of instructions – written in proteins and enzymes – that tell each cell of the body which genes should be expressed,” said Dr. Dressler. “The idea that cell state is a stable phenomenon is what is being challenged here. We believe these findings could eventually lead to drug treatments to fight this type of cell destabilization.”

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University of Michigan