FOCUS | September 16, 2005 | EPIGENETICS: Novel Players Identified in Gene Regulation

Trimming methyl groups from histones, the proteinaceous bobbins around which DNA is wrapped, is more dynamic than scientists once imagined. In the Sept. 16 Molecular Cell, HMS professor of pathology Yang Shi and his colleagues describe both positive and negative regulators of the lysine-specific demethylase LSD1, an enzyme that bundles DNA and silences genes by removing methyl groups from histones. The group’s findings shed light on how genes are switched on and off and may help clarify the missteps in gene regulation that can trigger disease processes, including malignancy.

Photo by Graham Ramsay
A recent study, headed by Yang Shi, identifies key regulators of the histone demethylase LSD1 and reveals a dynamic interplay among the proteins that manipulate chromatin structure and gene expression.

In a landmark study published last winter, Shi’s group identified LSD1 and provided the first tangible evidence that histone methylation, long thought to be an indelible mark, is in fact reversible. Now they reveal that the enzyme, part of a large multiprotein complex, is subject to the influence of its neighbors. The researchers observed that without these partners, LSD1 no longer demethylated histone–DNA packages. Yet when they replaced just one constituent protein, CoREST, normal activity was restored. Additional studies revealed that the cofactor could bind to LSD1 and that it also contained two SANT domains, protein motifs known to recognize histones lacking acetyl groups. The researchers also discovered that LSD1 prefers such deacetylated histones as its starting material for demethylation. Putting these pieces together, Shi’s team concluded that CoREST forms a bridge, connecting the demethylase to its histone–DNA substrate.

The researchers then wondered what might happen to LSD1 if this bridge were selectively removed from its surrounding cohort of proteins. Using RNA interference to diminish the levels of CoREST, they noted a corresponding reduction in the amount of LSD1 protein. Since this treatment did not change the quantity of LSD1 mRNA and could be counteracted by a proteasome-specific chemical inhibitor, the researchers believe that CoREST normally stabilizes its partner by protecting it from degradation.

This tug of war over demethylation “is adding another layer of regulation to epigenetic change.”

The investigators characterized two additional members of the LSD1 complex. One component, HDAC1/2, strips acetyl groups from histones and, like the demethylase, encourages gene silencing. Based on evidence that LSD1 favored underacetylated substrates, the scientists reason that HDAC1/2 acts first, snipping acetyl groups from histones. This deacetylation facilitates recognition by CoREST, which then, with LSD1 in tow, fosters subsequent histone demethylation. BHC80, another member of the complex, dampened demethylase activity when added in excess to LSD1/CoREST pairs, the researchers found. Shi and his team suggest that in contrast to the stimulatory effects of CoREST, BHC80 restrains LSD1 function. According to first author Yujiang Shi, a new faculty member at HMS, this tug of war over demethylation “is adding another layer of regulation to epigenetic change.”

—Nicole Davis

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