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Heart disease, leukemia links to dysfunctional nucleus

In cells, the nucleus keeps DNA protected and intact within an enveloping membrane. But a new study reveals that this containment influences how genes are expressed.

Using a suite of molecular technologies, Salk Institute scientists discovered two proteins sitting in the nuclear envelope that work together with the membrane to trigger key genes in DNA. Better understanding these intra cellular functions gives insight into diseases such as leukemia, heart disease and aging that appear related to dysfunction within the nuclear membrane.

Historically, the nuclear membrane's main purpose was thought to be keeping contents of the nucleus separated from the rest of the cell. Within the membrane, at least thirty different proteins — called nucleoporins — form openings (pores) in the membrane and control what goes in or out of the nucleus. But as the Hetzer lab shows, these nuclear pore complexes (NPCs), are not mere gateways into the nucleus, but regulators of DNA on the inside.

"Our research shows that, far from being a passive enclosure as many biologists have thought, the nuclear membrane is an active regulatory structure.

"Not only does it interact with portions of the genome to drive gene expression, but it can also contribute to disease processes when cell components are faulty."

Martin Hetzer PhD, Professor Molecular and Cell Biology Laboratory, holder of the Jesse and Caryl Philips Foundation chair, Salk Institute for Biological Studies, La Jolla, California, USA.

The work was conducted by Salk Institute scientists, and detailed in the November 2 issue of Genes & Development

"Discovering that key regulatory regions of the genome are actually positioned at nuclear pores was very unexpected," according to Arkaitz Ibarra PhD, Molecular and Cell Biology Laboratory, Salk Institute and first author of the paper. "And even more importantly, nuclear pore proteins are critical for the function of those genomic sites."

Curious about all regions of DNA with which nucleoporins interact, the team examined a human bone cancer cell line. Using a molecular biology technique called DamID, they pinpointed two nucleoporinsNup153 and Nup93 — and where they came into contact with the genome. Using several other sequencing techniques, they identified which genes were being affected in those regions — and how.

They discovered Nup153 and Nup93 interacted with stretches of the genome called super-enhancers, known to help determine cell identity. As every cell in our body has the same DNA, what differentiates a muscle cell from a liver cell or a nerve cell — is which genes are turned on or expressed within that cell.

The presence of Nup153 and Nup93 was found to regulate super-enhancer driven genes. Experiments that silenced either of these proteins resulted in abnormal gene expression from these regions.

Experiments in a lung cancer cell line validated the bone cancer results. Nucleoporins in the NPC were found to interact with multiple super-enhancer regions and drive gene expression. Experiments that altered NPC proteins made related gene expression faulty, even while still performing their primary role as gatekeepers of the cell membrane.

"It was incredible to find that we could perturb the proteins without affecting their gateway role, but still have nearby gene expression go awry," says Ibarra.

The results support other work indicating problems in the nuclear membrane play a role in heart disease, leukemia and progeria, a rare premature aging syndrome.

"People have thought the nuclear membrane is just a protective barrier — which is maybe the reason it evolved in the first place. But there are many more regulatory levels we don't understand. It is an important area because so far, every membrane protein that has been studied and found to be mutated or mis-localized — seems to cause a human disease," adds Hetzer.

The organization of the genome in the three-dimensional space of the nucleus is coupled with cell type-specific gene expression. However, how nuclear architecture influences transcription that governs cell identity remains unknown. Here, we show that nuclear pore complex (NPC) components Nup93 and Nup153 bind superenhancers (SE), regulatory structures that drive the expression of key genes that specify cell identity. We found that nucleoporin-associated SEs localize preferentially to the nuclear periphery, and absence of Nup153 and Nup93 results in dramatic transcriptional changes of SE-associated genes. Our results reveal a crucial role of NPC components in the regulation of cell type-specifying genes and highlight nuclear architecture as a regulatory layer of genome functions in cell fate.

Other authors on the paper were Swati Tyagi of the Salk Institute, Chris Benner of the University of California, San Diego, and Jonah Cool of Organovo Holdings, Inc.

Keywords: nuclear architecture nucleoporin nuclear pore complex cell identity superenhancer transcription

Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.287417.116.

Received July 17, 2016.— Accepted October 7, 2016.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

The work was funded by the Human Frontier Science Program, National Institutes of Health grant R01GM098749, NIH Transformative Research Award R01NS096786, the Glenn Foundation for Medical Research, the NOMIS Foundation, the Keck Foundation and American Cancer Society Award number P30CA014195.

About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

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Nov 14, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

A super-enhancer driven cell identity gene (RED DOT) localized in close proximity to the
nuclear envelope (GREEN) in the nucleus of a human primary lung fibroblasts (BLUE).

Image Credit:
Salk Institute for Biological Studies


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