Agriculture News

October 12, 2016

Key epigenetic switch mechanism in gene regulation discovered

WEST LAFAYETTE, Ind. - A Purdue University study pinpointed an epigenetic mechanism that is a key factor in how genes are switched on and off.

Both genetic and epigenetic mechanisms regulate human gene expression. External or environmental factors, such as carcinogens from tobacco smoking, disrupt normal epigenetic regulation. This leads to changes in gene expression, which results in the production of cancerous cells.

Humaira Gowher, a Purdue assistant professor of biochemistry, is interested in the mechanisms that control gene expression by directing epigenetic regulators such as DNA methylation to specific portions of a gene.

Gene expression is controlled by its genetic regulatory elements called promoters and enhancers. When cells need to express a specific gene, its enhancer element interacts with its promoter to stimulate the activation process. When a gene needs to be turned off or repressed, its specific enhancer is disengaged from the promoter.

DNA methylation refers to the addition of a methyl group to one of the bases of the DNA, cytosine, converting it into a methylcytosine. Presence of methylcytosine at the promoters and enhancers of genes signals the associated gene to be inactive.

DNA methylation is catalyzed by the enzymes called DNA methyltransferases or Dnmts.

Gowher and her team found that these Dnmts are important for releasing enhancers during gene repression and determined that a particular enzyme acts as a type of relay switch where the activity of one enzyme turns on the activity of the next, ultimately triggering an enzyme called Dnmt3a to methylate DNA in a specific location.

"The process we discovered provides a way for cells to control the activity of Dnmts at specific enhancers where DNA methylation must be deposited to ensure that genes are turned off when required," said Gowher, whose findings were published in the journal Nucleic Acids Research.

Gowher and her team studied this mechanism for a class of genes named pluripotency genes, which are expressed in stem cells. Stem cells replicate rapidly and stay in an undifferentiated state until they get an assignment and become a particular type of cell. During the process of cell differentiation, the pluripotent genes are turned off and DNA methylation occurs.

When external or environmental factors act on differentiated cells, DNA methylation can be disrupted, triggering a pluripotent state that leads to rapid proliferation of now damaged and cancerous cells.

"Understanding the way that cells regulate these mechanisms of repression may be able to help us understand what is being damaged and what we can watch for that can turn these genes back on," Gowher said.

Gowher said future research will involve looking further upstream in the process, particularly at the signals that can modulate the activity of these enzymes.

The paper is available at http://dx.doi.org/10.1093/nar/gkw426.

The Purdue College of Agriculture and the Purdue University Center for Cancer Research funded the study. 

Writer: Brian Wallheimer, 765-532-0233, brian.wallheimer@gmail.com

Source: Humaira Gowher, 765-494-3326, hgowher@purdue.edu 


ABSTRACT

An epigenetic switch regulates de novo DNA methylation at a subset of pluripotency gene enhancers during embryonic stem cell differentiation

Christopher J. Petell1, Lama Alabdi1, Ming He1, Phillip San Miguel3, Richard Rose1 and Humaira Gowher1,2,*

1Department of Biochemistry, Purdue University, West Lafayette, IN

2Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN

3DNA Sequencing Core Facility, Purdue University, West Lafayette, IN

Coordinated regulation of gene expression that involves activation of lineage specific genes and repression of pluripotency genes drives differentiation of embryonic stem cells (ESC). For complete repression of pluripotency genes during ESC differentiation, chromatin at their enhancers is silenced by the activity of the Lsd1-Mi2/NuRD complex. The mechanism/s that regulate DNA methylation at these enhancers are largely unknown. Here, we investigated the affect of the Lsd1-Mi2/NuRD complex on the dynamic regulatory switch that induces the local interaction of histone tails with the Dnmt3 ATRXDNMT3-DNMT3L (ADD) domain, thus promoting DNA methylation at the enhancers of a subset of pluripotency genes. This is supported by previous structural studies showing a specific interaction between Dnmt3-ADD domain with H3K4 unmethylated histone tails that is disrupted by histone H3K4 methylation and histone acetylation. Our data suggest that Dnmt3a activity is triggered by Lsd1-Mi2/NuRDmediated histone deacetylation and demethylation at these pluripotency gene enhancers when they are inactivated during mouse ESC differentiation. Using Dnmt3 knockout ESCs and the inhibitors of Lsd1 and p300 histone modifying enzymes during differentiation of E14Tg2A and ZHBTc4 ESCs, our study systematically reveals this mechanism and establishes that Dnmt3a is both reader and effector of the epigenetic state at these target sites.


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