Navigation Links
How major signaling pathways are wired to our genome gives new insight into disease processes

FINDINGS: Whitehead Institute scientists have determined that master transcription factors determine the genes regulated by key signaling pathways. In this way, signaling pathways are targeted to genes that are most relevant to each cell type and tailor gene expression to control cell state, growth, differentiation, and death.

RELEVANCE: When signaling pathways operate properly, a cell receives instructions from its neighbors and the environment that tweak gene expression and control the cell's identity and function. But in a number of human diseases, including cancer, these signaling pathways can go awry, increasing cell proliferation and decreasing programmed cell death. By manipulating signaling pathways, scientists may find new ways to treat cancer or to push cells into more specialized states, such as neurons to treat nerve damage or insulin-producing beta cells for diabetes.

CAMBRIDGE, Mass. (October 27, 2011) Normal development, from fertilized egg to adult organism, depends on each cell receiving proper instructions from its environment. In response to such incoming information, receptors on a cell's surface send signals to the nucleus that tweak gene expression and control cellular function.

However, in a number of human diseases, including cancer, cell signaling pathways can go awry. Without the correct information making its way into the nucleus, gene expression is altered, often with dire consequences.

Although researchers have long understood the importance of these signaling pathways, the mechanism through which they actually affect gene expression had been unclear. In research published this week in the journal Cell, scientists in the lab of Whitehead Institute Member Richard Young describe how a protein acts as a courier, carrying a message from a receptor on the cell's surface to a master transcription factor on the cell's DNA. The courier then tailors expression of genes bound by master transcription factors.

The discovery sheds new light on the relationship between signaling pathways, gene expression, cell function, and diseaseat the same time revealing potential targets for therapeutic intervention and novel approaches for reprogramming neurons or insulin-producing beta cells to treat nerve damage or diabetes.

"This is a broad, simplifying concept that is key to understanding how the whole human system works and how the genome responds to the world around itthat each signaling pathway has its own signaling molecule that finds its way to that cell's type-specific master transcription factor," says Young, who is also a professor of biology at MIT. "This idea allows us to think clearly about what is going awry in disease and how we potentially can treat people by modifying these signaling pathways."

To tease apart how signaling pathways modulate gene expression, Alan Mullen, who is the Cell paper's first author and a visiting scientist in the Young lab, analyzed the transforming growth factor-beta (TGF-beta) signaling pathway in several types of mouse and human cells. In both developing and mature cells, the TGF-beta pathway is involved in numerous cell activities, including specialization, homeostasis, and programmed death. Yet, corrupted versions of the TGF-beta signaling pathway are frequently found in cancer cells, allowing the cancer cells to proliferate and escape normal programmed cell death.

Mullen knew that when the TGF-beta signaling pathway's receptor is triggered by an environmental change, it activates the SMAD3 protein, which somehow couriers the receptor's message to the cell's DNA. Previous research had also suggested that SMAD3 might interact with hundreds of different transcription factors to achieve the desired response to environmental input.

Looking at embryonic stem, muscle, and certain immune system cells, Mullen found that once inside the nucleus, the activated SMAD3 settles onto the DNA adjacent to a master transcription factor, the main switch that turns the genes specific to each cell type on or off. In embryonic stem cells, SMAD3 nestles next to the master transcription factor Oct4.

"We were really surprised when we looked at the data because SMAD3 wasn't distributed with many different transcription factors. Instead, it appeared to be following Oct4, which is one of the transcription factors that determines embryonic stem cell state," says Mullen. "The master transcription factors are expressed at very high levels and dominate the transcription machinery because there is so much of these factors."

In muscle cells and specific immune system cells, Mullen saw similar results. SMAD3 only bound to the DNA next to the master transcription factors Myod1 and PU.1, respectively. Once associated with SMAD3, the master transcription factors adjust the nearby genes' expression.

Mullen's work indicates that a signal from one signaling pathway can interact with different master transcription factors in different cell types, which explains why the same signal can have distinct effects in multiple cell types. And the signal interacts with just one or a few master transcription factors in each cell typenot hundreds of transcription factors.

Related research from Young postdoctoral researcher Lee Lawton and graduate student Zi Peng Fan, who collaborated with the lab of Leonard Zon at Children's Hospital Boston, supports Mullen's findings. In an article in the same issue of Cell, the team's work with maturing blood cells shows that the BMP and Wnt signaling pathways use their respective signal molecules throughout the blood maturation process, but that the signals target various master transcription factors based on the cells' stage in this process.


Contact: Nicole Giese
Whitehead Institute for Biomedical Research

Related medicine news :

1. Policymakers should prepare for major uncertainties with Medicaid expansion
2. Ghost Writing Persists in Major Medical Journals
3. Teenage girls and senior students suffered highest levels of PTSD after major earthquake
4. Harvard Medical School launches major initiative to address crisis in drug development
5. Alcohol, Obesity Major Causes of Sudden Heart Death
6. Prevention measures needed to address major risk of falls after stroke
7. Major HIV prevention trial in women to drop oral tenofovir arm
8. Major grant awarded for HIV prevention study in Africa
9. Researchers find process that clears cholesterol and could reverse major cause of heart attack
10. Major ALS breakthrough
11. Major advanced cancer study to be led by Uppsala University
Post Your Comments:
(Date:11/30/2015)... VA (PRWEB) , ... November 30, 2015 , ... ... Research Foundation (Meso Foundation) released information for caregivers and held two webinars on ... are available on demand free of charge at . , With ...
(Date:11/30/2015)... Irving, TX (PRWEB) , ... November 30, 2015 ... ... for plastic surgery and dermatology, is proud to announce that its ThermiRFR temperature ... Europe. , ThermiRF is an innovative multi-application radiofrequency platform which uses temperature as ...
(Date:11/30/2015)... ... November 30, 2015 , ... The Museum of ... ushering in a new era of publicly accessible automated technology. Now, by popular ... to offer guests an up-close look at the shuttle at MOSI’s main entrance. ...
(Date:11/30/2015)... ... November 30, 2015 , ... On Saturday, October 24th, 2015, at ... an annual fundraising event, a 5K walk known as “Making Strides Against Breast Cancer”. ... abuse which is also located in Battle Creek, joined in for this campaign that ...
(Date:11/30/2015)... ... 2015 , ... During the week of Thanksgiving, the Mesothelioma ... its research, education, support, and advocacy efforts. The campaign is held every year-end ... Applied Research Foundation, which also goes by Meso Foundation, holds the highest ...
Breaking Medicine News(10 mins):
(Date:11/30/2015)... , Nov. 30, 2015  QT Vascular Ltd., ... and together with its subsidiaries, TriReme Medical LLC and ... company engaged in the design, assembly and distribution of ... vascular disease, is pleased to announce that a three-judge ... Court of Appeals for the Federal Circuit ("Federal Circuit") ...
(Date:11/30/2015)... Nov. 30, 2015  DURECT Corporation (Nasdaq: ... Matt Hogan , Chief Financial Officer, will ... on Tuesday, December 8 at 2:45 pm ... at the Westin Grand Central Hotel in ... for one-on-one meetings at this conference; interested ...
(Date:11/30/2015)... DUBLIN , Nov. 30, 2015 ... addition of the "Orphan Drugs Market 2015-2019" ... ) has announced the addition of the ... their offering. --> Research and Markets ... the "Orphan Drugs Market 2015-2019" report ...
Breaking Medicine Technology: