Chaos in the cell's command center

Images of cells with LSD1 activity on and off

In an experiment to determine the role lysine-specific demethylase 1 (LSD1) plays as embryonic stem cells (ESCs) differentiate into other cell types, Whitehead researchers tested for embryonic mouse cells to see what happens when LSD1's activity is blocked.  "Phase" indicates how cells appear under a microscope, and DNA is stained blue using Hoechst (Hoe). In ESCs with the gene Oct4 (stained green) turned off (ESCs + Dox), the cells are missing SSEA-1 (stained red), a marker found in pluripotent ESCs. In cells with LSD1 turned off (ESCs + Dox, TCP), the cells retain some of their SSEA-1 and remain pluripotent, indicating that LSD1 is required for ESCs to silence the ESC gene expression program completely. 

Image: Courtesy of Nature 482, 221–225.

February 1, 2012

Tags: Young LabGenetics + GenomicsProtein Function

CAMBRIDGE, Mass. – A defective operating system is never a good thing.

Like computers, our cells depend on operating systems to drive normal functions. Gene expression programs comprise the software code our cells rely on, with each cell type controlled by its own program. Corrupted programs can trigger disease.

Cellular operating systems can be corrupted by viruses, mutations, or malfunctions that occur as cells change from one type to another. Unlike computers that can use one operating system for their entire existence, differentiating cells need to switch operating systems as they mature­—from stem cell to, for example, nerve or muscle cell. In simple terms, differentiation requires two key steps: the genes active in the initial operating system must be deactivated; and the genes of the new cellular operating system must be turned on. If the switch is not flawless, a transitioning cell may die or be driven by a disease-causing program.

New research from Whitehead Institute scientists reveals the critical role one enzyme, lysine-specific demethylase 1 (LSD1), plays as embryonic stem cells differentiate into other cell types. Their research is published online this week in the journal Nature.

LSD1 was known to be critical to development, but little was known about the key role it plays during differentiation, when operating systems are switched.

"We knew that cells express a new set of genes when the operating switch occurs," says Steve Bilodeau, one of the Nature paper's authors and a postdoctoral researcher in the lab of Whitehead Member Richard Young. "But this study shows it is also essential to shut off genes that were active in the prior cell state. If you don't, the new cell is corrupted."

By investigating gene silencing during cell state transitions, Bilodeau and Warren Whyte, a Young lab graduate student and co-author of the Nature paper, redefined LSD1's role and described a previously unknown mechanism for silencing genes.

When they looked at the embryonic stem cell operating system genes that must be turned off during differentiation, Whyte and Bilodeau found LSD1 poised on the stem cell genes' enhancers, short bits of DNA that act as a landing pad for the proteins that enhance a gene's transcription and ultimately its protein production. When LSD1 receives the signal that the stem cell is transitioning into a more differentiated state, the enzyme pops into action and silences the ESC genes' enhancers. With their enhancers no longer operational, transcription of the stem cell genes is silenced, shutting down the stem cell operating system. As this occurs, other mechanisms switch on the cell's new operating system.

"This reveals the critical function of LSD1 in cell differentiation," says Whyte. "The enzyme decommissions the stem cell enhancers, thus allowing the new cell to function entirely within the parameters of the new operating system."

Although the work focuses on one enzyme's job in normal cells, Young sees broader implications. LSD1 is a member of a class of molecules that regulate both gene activity and chromosome structure, so the findings about LSD1 could give insight into how related regulators function. Also, knowing how a mechanism operates in normal cells provides a solid foundation for teasing apart what is going wrong in abnormal cells.

"This new knowledge brings us one important step closer to understanding defective operating systems in diseases such as cancer," says Young. "And this may give us a new angle on drug development for these diseases."

This work was supported by the Canadian Institutes of Health Research (CIHR), the Medical Research Council, and the National Institutes of Health (NIH).

Written by Nicole Giese Rura

* * * 

Richard Young's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

* * *

Full Citation:

"Enhancer Decommissioning by LSD1 During Differentiation of Embryonic Stem Cells"

Nature, published online February 1, 2012.

Warren A. Whyte (1,2*), Steve Bilodeau (1*), David A. Orlando (1), Heather A. Hoke (1,2), Garrett M. Frampton (1,2), Charles T. Foster (3,4), Shaun M. Cowley (4) and Richard A. Young (1,2).

1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Department of Molecular Biology, Adolf-Butenandt Institut, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
4. Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK
* These authors contributed equally to this work.

Whitehead Institute is a world-renowned non-profit research institution dedicated to improving human health through basic biomedical research.
Wholly independent in its governance, finances, and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology
through its faculty, who hold joint MIT appointments.

© Whitehead Institute for Biomedical Research         Nine Cambridge Center    Cambridge, MA 02142