Chromatin, the repeating polymer of DNA and associated histone proteins, is the physiological template of our genome. As such, elaborate mechanisms have evolved to introduce meaningful variation into chromatin for purposes of altering gene expression and other important biological processes. Covalent histone modifications, chromatin remodeling by ATP-dependent complexes and utilization of histone variants are three major mechanisms by which variation can be introduced into the chromatin fiber.

Dr. Allis and his colleagues favor the view that distinct patterns of covalent histone modifications form a “histone or epigenetic code” that is then read by effector proteins to bring about distinct downstream events. Histone proteins, their posttranslational modifications and the enzyme systems responsible for bringing them about are highly conserved through evolution. Members of the Allis lab are currently investigating different histone modifications and their biological roles in a variety of unicellular and multicellular eukaryotic models.

The Allis laboratory focuses on how chemical changes to histone proteins affect gene expression. Through such enzymatic processes as acetylation, methylation, phosphorylation or ubiquitylation, histones are believed to function like a master on/off switch and determine whether particular genes are active or inactive. Knowing how to control which genes to turn on or off, using therapy, could reduce the risk of certain diseases by activating genes that suppress tumor growth and deactivating genes that support it. The implications of this research for human biology and health are far-reaching.

Recent research from the Allis lab has shown that a robust “on” epigenetic mark, H3 lysine 4 methylation (H3K4me), a mark “written” by the human mixed lineage leukemia protein (MLL) and “read” by the nucleosome remodeling complex NURF (nucleosome remodeling factor) engages tri-methylated lysine 4 using a specific PHD finger in its BPTF subunit. In collaboration with colleagues at Sloan-Kettering Institute, the co-crystal structure of this PHD finger in complex with the H3K4me3 peptide has been solved at atomic resolution giving new insights into how these modules function in reading the histone code.

Dr. Allis and his colleagues hypothesized — and experimentally verified — that lysine/threonine or lysine/serine pairs act like “binary molecular switches” in modifying histone-effector interactions. Dr. Allis and his colleagues also observed frequent, high density posttranslational modifications, which they hypothesize are placed in strategic locations along the histone tail as a way for the cell to deal, in a reversible way, with gene silencing or perhaps gene activation. Dr. Allis and colleagues also have documented “cross-talk” relationships in the same histone tails (cis) or across distinct histone (trans) tails. It appears that these regulatory pathways govern chromatin function during DNA replication and repair, chromosome segregation (in meiosis and mitosis) and chromatin compaction as cells undergo programmed cell death or apoptosis.

Recent studies in budding yeast documented a histone modification pathway associated with RNA polymerase II (polII) transcription, whereby ubiquitylation of histone H2B leads to methylation of histone H3 on specific lysine residues. The findings suggest that ubiquitylation of H2B affects transcription elongation and nuclear architecture through its effects on chromatin dynamics.

In addition, research in the Allis lab has led to a recent proposal that the mammalian genome is indexed by histone H3 variants in a nonrandom fashion that reflects the assembly mechanisms of dedicated “personalized’’ chaperone proteins and exchange factors that control whether genes are constitutively expressed or remain silent. Efforts are underway to examine this “histone variant barcode” in the mouse (cells and animals) during defined pathways of differentiation.

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