In Nature paper, scientists at U.Va. health system crack part of 'histone' code

01/12/05

CHARLOTTESVILLE, Va., Jan. 12, 2005 Little is known about the specific role of histones - the protein 'spool' around which the famous DNA double helix is folded.

Now, researchers at the University of Virginia Health System have unraveled one mystery about what histones accomplish in the complex chemical cascade that determines the function of a cell in the body. Their findings are published in the Jan. 12, 2005 online edition of the journal Nature.

Scientists at U.Va's Department of Biochemistry and Molecular Genetics discovered that a previously known protein called Chd1 recognizes a flag (or code) on histones and physically binds to a certain mark (a methylation mark.) The protein Chd1 then attracts a huge complex of other proteins, called SAGA, that can turn genes on in the cell nucleus.

"This is a good example of how proteins respond to the histone code," explained study senior author Patrick Grant, PhD, an Assistant Professor of Biochemistry and Molecular Genetics at U.Va. "There is a theory, proposed by Dr David Allis at Rockefeller University and Dr Brian Strahl at the University of North Carolina, that DNA does not function in isolation. Rather, its' function can be dictated by this modification of histones, which can determine whether DNA is exposed and accessible or not. This takes us one step closer to understanding how chemical information carried on histones, rather than DNA, is recognized and read during the regulation of genes."

Chd1 mutation has been linked to a rare neurological disease called CHARGE syndrome that causes birth defects, including eye abnormalities, facial palsy and swallowing problems, blocked nasal passages, heart defects and delayed development. Already, Grant and his colleagues are working in the lab on a project involving the role of SAGA proteins in another rare neurological disorder called spinal cerebellar ataxia type 7 that causes neurodegeneration and blindness. Grant believes that Chd1 and SAGA interaction may be vital for normal brain development and function.

Grant said that, until his discovery, there have been very few proteins identified that recognize these methylation marks on histones. He said information has recently emerged about how genes can be turned off by histone methylation and how abnormal chemical modification of histones may underlie the formation of certain cancers. "This research adds important knowledge to our understanding of how cells signal to turn genes on," Grant said.

Contributors to the research in Nature with Grant were Marilyn G. Pray-Grant and Jeremy A. Daniel, both of the Department of Biochemistry and Molecular Genetics at U.Va. and scientists at the Diversa Corp. and the Scripps Research Institute. January 12, 2005

Source: Eurekalert & others

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