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Research

Our current focus is on the molecular mechanisms of epigenetics, that is, the extra-genetic information that gives rise to the different patterns of gene expression that distinguish different cells of an organism. Since all the cells of an individual contain identical DNA, the different patterns of genes they express come about, in part, by how tightly the different regions of the DNA are packaged. This packaging of the DNA can either be an obstacle to gene expression or can be a loose assemblage that allows RNA polymerase access to the DNA to be transcribed. Different regions of the genome are packaged differently to give rise to distinct tissues and this occurs during development. These patterns of gene expression are then maintained in adult cells and, importantly, this extra-genetic information is transferred to daughter cells after cell division so that the tissue specificity is again maintained.

One critical aspect of how this packaging is regulated involves specific modifications placed on the histone proteins around which the DNA is wrapped. The histones can be modified at their N-terminal tails and these modifications include acetyl-groups, phosphates and methyl-groups. In fact, some of these modifications can affect other modifications being placed on the same histone protein demonstrating the intricacies and dynamics inherent to the regulation of this process.

Of particular interest for our studies are the enzymes responsible for placing methyl modifications on lysine residues of histone proteins. Some methyl modifications appear to be very stable and therefore their presence might account for the heritability of patterned gene expression. We are studying the factors required to achieve higher-order genome structures as well as the regulation and capabilities of the enzymes that place methyl groups, and how and when they are targeted to different histones on the DNA.

Given that tumorigenesis is a prime example of misregulated gene expression patterns, studies of the molecular basis of epigenetics would pertain to aberrant as well as normal cellular identity. As an example, the levels of one of the histone lysine methyltransferases under study are up-regulated in later stages of prostate cancer, specifically when the cancer becomes metastatic. We are currently investigating the function of this histone lysine methyltransferase using mouse-model systems. For more information, please click the webpage link on top of this page.

 


Regulation of Gene Expression in Eukaryotes

Summary: Danny Reinberg studies the regulation of gene expression in eukaryotes.Gene expression – the process that cells use to produce proteins from genes on DNA strands – is fundamental to all life. DNA sequences in genes are first “transcribed” to RNA molecules, which then become the templates for proteins. But this process must be controlled so that correct amounts and types of proteins are made in a normal cell. Moreover, in multicellular animals, the complex regulation of gene expression that results in different tissues during development and maintains tissue identity in the adult must be established.

Transcription_Cycle_Intro

In any tissue of the body, there are some genes that are never expressed – they are “silent” genes – and there are some genes that are expressed exclusively to this tissue, giving rise to its particular functions and identity. Somehow, when a cell in one organ divides, the identity of the organ is transmitted accurately to the daughter cells that now also exhibit this differential gene expression. How does this happen? This transmission of identity is not through the genes themselves, as all cell types contain the identical genetic makeup. Instead, this complex and fascinating process is functionally dependent on the proteins that structure the body of DNA. My laboratory’s long-term goal is to determine how a gene gets transcribed when it does, and what controls this process. To do this, we set out to determine the criteria that enable or disable transcription as a function of increasingly complex gene organization.

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A Biochemist by Nature
by Karen Hopkin

Danny Reinberg has broken down everything from transcription factors to chromatin. Then he builds them back up, and the discoveries come.Danny Reinberg is a biochemist—a hard-core, purebred, columns-in-the-cold-room kind of biochemist. Born in Santiago, Chile, in 1954, Reinberg took his first biochemistry course as an undergraduate at the Catholic University in nearby Valparaiso. “I liked it so much that even though I got an A-minus, I went back and said, ‘You know, I don’t think I have a complete understanding and grasp of biochemistry. I’d like to take the course again.’” The professor, says Reinberg, “looked at me and said, ‘You’re crazy! Nobody wants to take it again.’” Although his grade actually went down the second time around, Reinberg says, “I loved it.”

That same passion for all things biochemical—and for protein purification in particular—has served Reinberg well. Now a Howard Hughes Medical Institute investigator at the New York University School of Medicine, Reinberg made a name for himself in the field of transcription by isolating the “factors that get together to form the monstrous apparatus that transcribes protein-coding genes,” says Rick Young of the Whitehead Institute. “Because of the sheer number and complexity of these components, purifying them and characterizing their activities was a biochemical tour de force.” Reinberg has since applied that same level of rigor, says Young, “to characterizing the factors that modify chromatin in the vicinity of the transcription apparatus and thereby contribute to gene regulation.”“I think Danny is one of the best people working in the chromatin/transcription field—and it’s a pretty big field with a lot of very good people,” adds Bob Tjian of the University of California, Berkeley. “He’s just a really good protein biochemist who knows how to purify proteins. That was—and is—a big advantage if you want to get down to the mechanistic aspects of complicated reactions and complex molecular machinery.”

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